slow border cells



SLBO protein is expressed predominantly during late embryogenesis in the nuclei of a restricted set of differentiating cell types, such as the lining of the gut and epidermis, similar to the mammalian tissues that express C/EBP. The earliest expression is at 9-10 hours postfertilization in cells associated with the posterior spiracles. The highest levels are found at 12-18 hours, first in the salivary gland, and then in the proventriculus and midgut. Lower levels of expression are found in the foregut, hindgut and epidermis (Rorth, 1992).


Staining in border cell nuclei is evident early in stage 9, just prior to border cell migration. Staining in the leading centripetal follicle cells is also nuclear and is detected at stage 10, just prior to their migration (Montell, 1992).

Effects of Mutation or Deletion

Mutations in the slbo gene cause late embryonic lethality. Embryos that lack slbo die just before or just upon hatching. The lethal phenotype of C/EBP mutants can be rescued with the cloned C/EBP gene introduced by P-element-mediated germ-line transformation (Rorth, 1992).

The involvement of Breathless (a Drosophila FGF receptor tyrosine kinase homolog) in border cell migration has prompted an inquiry as to whether RAS, a downstream effector for receptor tyrosine kinases, contributes to receptor tyrosine kinase-mediated motility. A dominant-negative RAS protein inhibits cell migration when expressed specifically in border cells during the period when these cells normally migrate. When expressed prior to migration, dominant-negative RAS promotes premature initiation of migration. Conversely, expression of constitutively active RAS prior to migration results in a significant delay in the initiation step. Furthermore, the defect in initiation of border cell migration found in slbo1, a mutation at the locus that encodes Drosophila C/EBP homolog, is largely rescued by reducing RAS activity in border cells prior to migration. Taken together, these observations indicate that RAS activity plays two distinct roles in the border cells: (1) reduction in RAS activity promotes the initiation of that migration process and (2) RAS activity is required during border cell migration. The possible involvement of two downstream effectors of Ras in border cell migration was also examined. Raf activity was dispensable to border cell migration while reduced Ra1 activity inhibited initiation. Ra1 is a small GTPase that is activated by RAS. Therefore, RAS plays a critical role in the dynamic regulation of border cell migration via a Raf-independent pathway. It is believed that reducing RAS activity bypasses the normal requirement for SLBO expression for cell migration. The alternative explanation, that SLBO activates the expression of specific receptor tyrosine kinases, is here held to be untenable (Lee, 1996).

During Drosophila oogenesis, spatially restricted activity of the Epidermal growth factor receptor tyrosine kinase first recruits follicle cells adjacent to the oocyte to a posterior cell fate and subsequently, in a later function, specifies dorsal follicle cell fate. Gurken is known to act as the ligand stimulating Egf-r in both instances. Another receptor tyrosine kinase, Breathless, stimulates migration of the anterior follicle cells known as border cells. Since Ras is known to mediate many receptor tyrosine kinase effects, the role of Ras was investigated in follicle cell fate determination, differentiation, and migration throughout oogenesis. Early ectopic Ras activity induces transient expression of posterior follicle cell markers in anterior follicle cells, but does not inhibit anterior differentiation. Among the posterior follicle cell markers is the gene pointed expressed in anterior follicle cells during stages 8 and 9 after being subjected to ectopic Ras during stage 2. Later ectopic Ras activity inhibits anterior follicle cell differentiation but does not induce posterior marker expression. Complete transformation of anterior follicle cells to posterior follicle cells required early ectopic Ras activity in egg chambers where terminal differentiation of anterior cells is inhibited. Although Ras alone is insufficient to completely transform anterior cells into posterior cells, complete transformation of anterior cells to posterior cells does occur when transient Ras activity is induce in a slow border cells (slbo) mutant. Thus Ras and C/EBP play antagonistic roles in the terminal differentiation of border cells (T. Lee, 1997).

slbo targets breathless and is essential for terminal differentiation and migration of the anterior follicle cells known as border cells. Ectopic Ras activity prior to stage 6 of oogenesis impairs border cell migration. An additional copy of slbo is able to rescue the border cell migration defect in egg chambers with elevated ras, indicating that increased C/EBP expression counteracts increased Ras activity. It is concluded that Ras and C/EBP appear to antagonize each other in the terminal differentiation of border cells, and that it does not appear that low Ras activity per se is required for initiation of border cell migration (T. Lee, 1997).

Two other cell populations were studied: dorsal follicle cells and outer follicle cells. It was found that activated Ras is sufficient to specify dorsal follicle cell fate. In addition, a surprising role for border cells was found in the establishment of outer follicle cell fate. During stage 9, follicle cells covering the nurse cells gradually flatten, and, simultaneously, most follicle cells undergo movement from anterior to posterior and finally form a columnar epithelium in contact with the oocyte. These columnar epithelial cells constitute the outer follicle cells of the oocyte. Interestingly, outer follicle cell rearrangement is impaired when border cell fate is suppressed by activated Ras. These results suggest that, in vivo as in vitro, Ras can have diverse effects on different cells, but, in addition, Ras activity can have different effects on the same cells at different stages in their development (T. Lee, 1997).

Cells migrating through a tissue exert force via their cytoskeleton and are themselves subject to tension, but the effects of physical forces on cell behavior in vivo are poorly understood. Border cell migration during Drosophila oogenesis is a useful model for invasive cell movement. This migration requires the activity of the transcriptional factor Serum response factor (SRF) and its cofactor MAL-D and evidence is presented that nuclear accumulation of MAL-D is induced by cell stretching. Border cells that cannot migrate lack nuclear MAL-D but can accumulate it if they are pulled by other migrating cells. Like mammalian MAL, MAL-D also responds to activated Diaphanous, which affects actin dynamics. MAL-D/SRF activity is required to build a robust actin cytoskeleton in the migrating cells; mutant cells break apart when initiating migration. Thus, tension-induced MAL-D activity may provide a feedback mechanism for enhancing cytoskeletal strength during invasive migration (Somogyi

To investigate conditions for MAL-D nuclear accumulation, border cells genetically unable to initiate migration were analyzed. slbo is a transcription factor that is required for border cell migration. None of the clusters in which all cells were mutant for slbo (n = 20 clusters) had nuclear MAL-D, regardless of developmental stage. Thus, border cells that were genetically unable to initiate migration were unable to accumulate nuclear MAL-D (Somogyi, 2004).

To determine whether the lack of nuclear MAL-D in slbo mutant cells was due to cell genotype or due to the physical state of the cell, an in vivo 'pulling experiment' was performed. This experiment takes advantage of the fact that border cells migrate as a cluster of strongly adherent cells and not as individual cells. If nonmigratory slbo mutant cells are found in a border cell cluster with wild-type cells, the mutant cells can be pulled along by the wild-type cells. This 'piggy-back' behavior is observed for a variety of different mutants affecting border cell migration -- in fact, it occurs in all genotypes that have been tested. The slbo mutant cells are always in the rear and delay migration of the border cell cluster in proportion to their abundance. Thus, the mutant cells do not become migratory as such but are pulled along by the actively migrating cells. Remarkably, slbo mutant cells that were pulled into migration by wild-type cells did accumulate nuclear MAL-D. They did so at a frequency similar to that of wild-type migrating cells. Migration of mixed clusters is often delayed and may occur during stage 9 or stage 10. In both situations, nuclear MAL-D accumulation was observed. Finally, even mutant cells that had not (yet) invaded the germline could be positive if attached to migrating wild-type cells. This, together with the observations in wild-type cells, shows that border cell position does not control MAL-D accumulation. Thus, nuclear MAL-D accumulation is not directly dependent on cell genotype, on cell position, or on developmental stage. However, nuclear MAL-D accumulation is only observed in nonmotile mutant border cells if they are being pulled by other cells. These results support the idea that cell deformation or perceived tension regulates MAL-D accumulation (Somogyi, 2004).

Notch signaling links interactions between the C/EBP homolog slow border cells and the GILZ homolog bunched during cell migration

In the follicle cell (FC) epithelium that surrounds the Drosophila egg, a complex set of cell signals specifies two cell fates that pattern the eggshell: the anterior centripetal FC that produce the operculum and the posterior columnar FC that produce the main body eggshell structure. The long-range morphogen DPP represses the expression of the bunched (bun) gene in the anterior-most centripetal FC. bun, which encodes a homolog of vertebrate TSC-22/GILZ, in turn represses anterior gene expression and antagonizes Notch signaling to restrict centripetal FC fates in posterior cells. From a screen for novel targets of bun repression, the C/EBP homolog slow border cells (slbo) has been identified. At stage 10A, slbo expression overlaps bun in anterior FC; by stage 10B they repress each other's expression to establish a sharp slbo/bun expression boundary. The precise position of the slbo/bun expression boundary is sensitive to Notch signaling, which is required for both slbo activation and bun repression. As centripetal migration proceeds from stages 10B-14, slbo represses its own expression and both slbo loss-of-function mutations and overexpression approaches reveal that slbo is required to coordinate centripetal migration with nurse cell dumping. It is proposed that in anterior FC exposed to a Dpp morphogen gradient, high and low levels of slbo and bun, respectively, are established by modulation of Notch signaling to direct threshold cell fates. Interactions among Notch, slbo and bun resemble a conserved signaling cassette that regulates mammalian adipocyte differentiation (Levine, 2007).

bunched refines a DPP activity gradient by antagonizing Notch signaling to establish the posterior edge of the operculum-forming centripetal FC. This study reveals that bunched is part of an intricate switch reliant on Notch activation of slbo to direct alternate FC fates. These observations contribute to a model in which bunched connects long-range morphogen cues to short range, cell contact-dependent signaling. Together with recent work on the bunched homologue GILZ in mammalian cell culture, these data suggest that this family of proteins is part of a conserved signaling cassette regulating cell fate decisions, as detailed below (Levine, 2007).

In different contexts cells migrate either as integrated sheets, such as during convergent extension, or as small groups of cells, such as during neural crest migration. During border cell migration from stages 8-10, a subset of anterior FC transiently loses epithelial polarity, delaminates and rounds into a small semi-polarized cell cluster that migrates through the nurse cell complex. In contrast, during centripetal migration from stages 10-14 a ring of anterior follicle cells changes shape and squeezes through the oocyte/nurse cell complex in a process coordinated with rapid nurse cell dumping. Marker gene expression indicates that the centripetal FC stretch to cover the anterior of the oocyte and retain epithelial contacts with the anterior and posterior nurse cell FC and columnar FC groups, respectively, throughout this mass cell ingression. While unique genetic pathways likely regulate these distinct cell migrations, because both the border cells and the centripetal FC coordinately migrate through the germ line cyst and arrive in the same vicinity at the anterior of the egg, it is unsurprising that common components are involved in both processes. Non-muscle myosin (zipper) and DE-cadherin (shotgun) are expressed and required for migration in both cell types. As well, it has been shown that slbo itself is required for DE-cadherin accumulation during both border cell and centripetal FC migrations, an observation consistent with the role for slbo function in the centripetal FC that are demonstrated in this study. Recently, screens for border cell-specific gene expression have identified many transcripts expressed in both tissues (Levine, 2007).

Comparing the role and regulation of slbo during the centripetal FC sheet and border cell cluster migrations reveals both shared and unique requirements. Weak slbo mutations, which completely block border cell migration, have no discernable effect on centripetal FC migration, which is disrupted only in stronger allelic combinations. While early slbo mutant clones reduced DE-cadherin accumulation in the dorsal anterior FC and in the border cells, late slbo mutant clones in the nurse cell FC and centripetal FC are difficult to recover and properly stage. These clones result in several effects on late stage egg chambers. First, these resulted in increased levels of DE-cadherin and decreased levels of DLG consistent with changes in epithelial polarity and adhesion. Second, large anterior slbo mutant clones are associated with a failure of centripetal FC ingression to coordinate with nurse cell dumping. It is noted that slbo mutant phenotypes are distinct from DE-cadherin shotgun (shg) mutants, which result in ectopic centripetal migration between posterior nurse cells. slbo mutants do resemble dlg mutant phenotypes associated with defects in FC shape and epithelial invasiveness. And third, ectopic slbo-lacZ expression associated with disintegration of the follicular epithelia and egg chamber collapse which are likely connected to defects in epithelial maintenance. Thus previous reports that the strong slbo allele has no effects on centripetal FC migration may result from difficulties recovering and staging these highly aberrant and friable late stage mutant egg chambers (Levine, 2007).

The mechanism of slbo regulation in the border cells and centripetal FC is also distinct. It has been shown that post-transcriptional regulation of slbo protein levels is critical to proper border cell migration but does not occur in the centripetal FC. This study shows that in both cell groups, Notch initiates slbo expression and slbo is necessary and sufficient to repress its own expression as centripetal migration proceeds. SLBO protein can bind to a DNA sequence element located near the start site of its own promoter, and several matches to the canonical C/EBP binding site occur as well in the sequence of the slbo2.6 element that is sufficient to mediate autorepression, so this regulation is likely direct. Thus slbo adopts two strategies to fine-tune its levels: post-transcriptional regulation specifically in the border cell and transcriptional autoregulation in the both cell groups, as shown in this study (Levine, 2007).

It has been shown that DPP establishes the position of the bun expression boundary in the anterior FC and this boundary coincides with the posterior edge of the operculum eggshell structure. This study shows that as this boundary forms, slbo and bun expression patterns initially overlap and subsequently slbo and bun repress each other's expression to resolve respective expression patterns into two distinct cell groups. Notch signaling plays a central role in these interactions: Notch activates slbo expression in the centripetal FC and bun is required to antagonize Notch activation in posterior cells adjacent to the boundary (Levine, 2007).

The position of the boundary is highly sensitive to Notch activity so that increased Notch signaling leads to increased slbo2.6 expression both in the centripetal FC and, surprisingly, in adjacent columnar FC. Ectopic slbo expression in Nintra-expressing columnar FC at stage 10B is not associated with changes in FC proliferation and thus the spread of Notch activity likely relies on cell–cell signaling. This may arise either from (1) Notch activation of slbo expression in a large group of centripetal FC precursors that is not subsequently downregulated to a more narrow domain or (2) a Nintra-dependent activation of Notch signaling in adjacent columnar FC leading to cell contact-dependent posterior spread of slbo expression. The latter explanation is preferred because slbo2.6GAL4 expression expanded to almost all columnar FC in many egg chambers. In this way the position of the DPP-dependent cell fate boundary that defines the operculum is quite flexible but always drawn sharply by Notch activation (Levine, 2007).

While several canonical bun and Suppressor of Hairy [Su(H)] binding sites are located in the slbo2.6 element indicating slbo regulation by bun1 and Notch signaling, respectively, might be direct, several observations indicate slbo regulation at the boundary by bun is likely more complex. It has been noted previously that: (1) high levels of Notch and Notch target gene expression occur in anterior FC, with slightly reduced levels in centripetal FC in contact with bun-expressing cells and (2) increased levels of Notch targets occur in all cells of bun mutant clones at the centripetal FC boundary except those that contact bun+ cells. A parallel relationship is observed between bun and the Notch target slbo: (1) reduced levels of slbo occur in cells adjacent to bun-expressing cells in WT egg chambers, and (2) slbo expression occurs in bun mutant clones located at the centripetal FC boundary, with lower slbo levels in bun cells in contact with bun+ cells. Thus while bun may repress slbo directly, bun also antagonizes Notch activation of slbo in a non-cell autonomous manner. Consistent with this, bun clones removed from the centripetal FC do not lead to increased slbo expression and bun1 is not sufficient to block Nintra activation of slbo2.6 in the centripetal FC (Levine, 2007).

Notch modulation of slbo expression may be indirect as well. Because the Nts; slbo01310/slbo01310 double mutant egg chambers retain strong slbo-lacZ expression throughout the FC compared to Nts; slbo01310/+ egg chambers stained in parallel, it is hypothesized that Notch blocks SLBO protein's ability to repress its own expression. In this scenario, which must be further tested, the rapid reduction in slbo expression as centripetal migration proceeds results from both (1) decreasing Notch activation of slbo via Su(Hw) sites in the slbo promoter and (2) relief of a block on slbo autorepression. Consistent with rapid changes in Notch levels in the migrating centripetal FC, as slbo levels decrease a corresponding increase is seen in the levels of Cut protein, a key target of Notch repression in these cells. Because reduced dorsal appendages and opercula are seen in Nintra-expressing egg chambers, it is likely that rapid reduction in Notch levels is critical to permit the further patterning of anterior structures (Levine, 2007).

Dynamic interactions among bun, slbo and Notch signaling tightly regulate DE-cadherin levels in the centripetal FC. bun mutant clones lead to increased Notch signaling and DE-cadherin accumulation and Nintra is sufficient to increase DE-cadherin levels in the FC. slbo mutant clones lead to loss of DE-cadherin expression early and ectopic DE-cadherin levels late. Thus a recurring theme is that tight modulation of DE-cadherin levels is required in the FC at late oogenesis for epithelial transitions including border cell migration, centripetal FC migration and dorsal appendage elongation (Levine, 2007).

Recently, it has been shown that the bun homolog GILZ antagonizes the ability of C/EBP to activate expression of the key fat cell master regulator gene PPARγ2 (Peroxisome Proliferator Activator γ2) in adipogenic mesenchymal stem cells (Shi, 2003). GILZ binds a promoter element required for C/EBP-mediated activation and recruits HDAC1 (Histone Deacetylase 1) to repress PPARγ2 expression and promote the osteogenic cell fate. GILZ can also directly bind to C/EBP in vitro. Shi (2003) proposes that a balance of GILZ repressor and C/EBP activator in precursor mesenchymal cells regulates levels of PPARγ2, the master fat cell regulator. The similarities between these pathways are striking and it is proposed they constitute a conserved signaling cassette required for cell fate commitment. In support of a role for Notch in both, it has been shown that Notch signaling promotes adipogenesis in tissue culture , although the specific role of Notch in adipogenesis has been questioned. Targets may be conserved as well: expression of a gene homologous to PPARγ2 in the centripetal FC has been noted. While a connection between border cell specification and adipogenesis has been noted, slbo has no role in fly fat body formatio. However, bun expression hduring fat body formation has been detected suggesting that portions of this fly signaling cassette may operate in a general pathway required for storage cell differentiation (Levine, 2007).

HNT mediates its effect on cluster cohesion via JNK and its effect on border cell motility primarily through STAT and SLBO

Cell movements represent a major driving force in embryonic development, tissue repair, and tumor metastasis. The migration of single cells has been well studied, predominantly in cell culture; however, in vivo, a greater variety of modes of cell movement occur, including the movements of cells in clusters, strands, sheets, and tubes, also known as collective cell migrations. In spite of the relevance of these types of movements in both normal and pathological conditions, the molecular mechanisms that control them remain predominantly unknown. Epithelial follicle cells of the Drosophila ovary undergo several dynamic morphological changes, providing a genetically tractable model. This study found that anterior follicle cells, including border cells, mutant for the gene hindsight (hnt) accumulated excess cell-cell adhesion molecules and failed to undergo their normal collective movements. In addition, HNT affected border cell cluster cohesion and motility via effects on the JNK and STAT pathways, respectively. Interestingly, reduction of expression of the mammalian homolog of HNT, RREB1, by siRNA inhibited collective cell migration in a scratch-wound healing assay of MCF10A mammary epithelial cells, suppressed surface activity, retarded cell spreading after plating, and led to the formation of immobile, tightly adherent cell colonies. It is proposed that HNT and RREB1 are essential to reduce cell-cell adhesion when epithelial cells within an interconnected group undergo dynamic changes in cell shape (Melani, 2008).

To explore the mechanisms by which HNT affects cluster cohesion and motility, its effects on known signaling pathways were investigated. In the extraembryonic tissue known as the amnioserosa, hnt is a negative regulator of the JNK signaling cascade. Recently, the JNK pathway was shown to be active in the border cells and to affect border cell migration in clusters with reduced PVR activity. In addition, inhibition of the JNK cascade causes a phenotype that strikingly resembles the cluster dissociation phenotype caused by HNT overexpression, suggesting that HNT could be a negative regulator of the JNK pathway or vice versa. By using phospho-Jun antibody staining as a readout of the JNK signaling cascade, the activity of this pathway was seen to be reduced in border cells overexpressing hnt. In clusters in which JNK was reduced by overexpression of either Puckered (the JNK phosphatase) or a dominant-negative form of Basket (Drosophila JNK), cluster disassembly reminiscent of the hnt gain-of-function phenotype was observed. In addition, HNT was upregulated 1.7- and 1.4-fold, respectively. Together, these results indicate that hnt and JNK repress each other. In the embryo, in which HNT also antagonizes JNK, this pathway is required for the turnover of focal complexes and proper dorsal closure. Therefore, HNT appears to play a general role in remodeling of adhesion complexes to facilitate morphogenesis (Melani, 2008).

Although the cluster-disassembly phenotype of HNT could be attributed to effects on JNK signaling, JNK pathway mutations caused milder border cell motility defects than hnt. To determine whether HNT affected, in addition, one of the known border-cell-motility pathways, the effect of hnt on the activity of STAT and its key target SLBO was examined. STAT activation and nuclear translocation is the most upstream event in the differentiation of the border cells and is also required throughout border cell migration. It was found that, in border cells overexpressing HNT, nuclear accumulation of STAT was reduced though not eliminated. In addition, the levels of slbo were dramatically reduced in border cells overexpressing HNT. Because loss of function of either STAT or SLBO causes a dramatic migration defect, the effects of HNT overexpression on STAT and SLBO can account for the severe effect on motility. However, neither stat nor slbo mutant border cells exhibit a cluster-disassembly phenotype. Therefore, it is concluded that HNT mediates its effect on cluster cohesion via JNK and its effect on border cell motility primarily through STAT and SLBO (Melani, 2008).

Although HNT overexpression affects border cell motility via effects on STAT and SLBO, HNT has general effects on cell adhesion and morphogenesis, whereas SLBO appears to be more specific. For example, the effects of hnt on stretched follicle cells and in embryonic tissues are independent of SLBO because this protein is neither expressed nor required in these other cell types. Therefore, it is proposed that HNT plays a general role in regulating cell adhesion and morphogenesis via JNK signaling and a tissue-specific role in motility through STAT and SLBO. In this way, HNT can cooperate with tissue-specific factors to orchestrate a diverse array of collective cell movements (Melani, 2008).


Alberini, C. M., et al. (1994). C/EBP is an immediate-early gene required for the consolidation of long-term facilitation in Aplysia. Cell 76: 1099-114

An, W. and Wensink, P. C. (1995a). Integrating sex- and tissue-specific regulation within a single Drosophila enhancer. Genes Dev 9: 256-266. PubMed citation: 7851798

An, W. and Wensink, P. C. (1995b). Three protein binding sites form an enhancer that regulates sex- and fat body-specific transcription of Drosophila yolk protein genes. EMBO J. 14(6): 1221-1230. PubMed citation: 7720712

Anderson, M.G., Perkins, G.L., Chittick, P., Shrigley, R.J. and Johnson, W.A. (1995). drifter, a Drosophila Pou domain transcription factor, is required for correct differentiation and migration of tracheal cells and midline glia. Genes Dev. 9(1): 123-37. PubMed citation: 7828848

Bauknecht, T., See, R. H. and Shi, Y. (1996). A novel C/EBP beta-YY1 complex controls the cell-type-specific activity of the human papillomavirus type 18 upstream regulatory region. J. Virol. 70(11): 7695-7705

Beccari, S., Teixeira, L. and Rorth, P. (2002). The JAK/STAT pathway is required for border cell migration during Drosophila oogenesis. Mech. Dev. 111(1-2): 115-23. 11804783

Begay, V., Smink, J. and Leutz, A. (2004). Essential requirement of CCAAT/enhancer binding proteins in embryogenesis. Mol. Cell. Biol. 24(22): 9744-51. 15509779

Borghese, L., et al. (2006). Systematic analysis of the transcriptional switch inducing migration of border cells. Dev. Cell 10: 497-508. 16580994

Buck, M., et al. (2001). C/EBPß phosphorylation by RSK creates a functional XEXD caspase inhibitory box critical for cell survival. Molec. Cell 8: 807-816. 11684016

Calella, A. M., et al. (2007). Neurotrophin/Trk receptor signaling mediates C/EBPalpha, -beta and NeuroD recruitment to immediate-early gene promoters in neuronal cells and requires C/EBPs to induce immediate-early gene transcription. Neural Develop. 2:4. Medline abstract: 17254333

Calkhoven, C. F., Muller, C. and Leutz, A. (2000). Translational control of C/EBPalpha and C/EBPbeta isoform expression. Genes Dev. 14(15): 1920-32.

Carmona, M. C., et al. (2002). Mitochondrial biogenesis and thyroid status maturation in brown fat require CCAAT/enhancer-binding protein alpha. J. Biol. Chem. 277(24): 21489-98. 11940593

Carnac, G., et al. (1998). RhoA GTPase and serum response factor control selectively the expression of MyoD without affecting myf5 in mouse myoblasts. Mol. Biol. Cell 9(7): 1891-1902

Chan, M. C., Nguyen, P. H., Davis, B. N., Ohoka, N., Hayashi, H., Du, K., Lagna, G. and Hata, A. (2007). A novel regulatory mechanism of the bone morphogenetic protein (BMP) signaling pathway involving the carboxyl-terminal tail domain of BMP type II receptor. Mol Cell Biol 27: 5776-5789. PubMed ID: 17576816

Chang, C. J., Chen, Y. L. and Lee, S. C. (1998). Coactivator TIF1beta interacts with transcription factor C/EBPbeta and glucocorticoid receptor to induce alpha1-acid glycoprotein gene expression. Mol. Cell. Biol. 18(10): 5880-5887

Chen, A., et al. (2003). Inducible enhancement of memory storage and synaptic plasticity in transgenic mice expressing an inhibitor of ATF4 (CREB-2) and C/EBP proteins. Neuron 39: 655-669. Medline abstract: 12925279

Chen, P.-L., et al. (1996). Retinoblastoma protein positively regulates terminal adipocyte differentiation through direct interaction with C/EBPs. Genes Dev. 10:2794-2804

Chen, S. S., Chen, J. F., Johnson, P. F., Muppala, V. and Lee, Y. H. (2000). C/EBPß, when expressed from the C/ebp{alpha} gene locus, can functionally replace C/EBPalpha in liver but not in adipose tissue. Mol. Cell Biol. 20: 7292-7299. 10982846

Chiu, C.-H., et al. (2004). Effect of a C/EBP gene replacement on mitochondrial biogenesis in fat cells. Genes Dev. 18: 1970-1975. 15289464

Croniger, C., et al. (1997). Role of the isoforms of CCAAT/Enhancer-binding protein in the initiation of phosphoenolpyruvate carboxykinase (GTP) gene transcription at birth. J. Biol. Chem. 272(42): 26306-26312.

Dixon, T. M., Daniel, K. W., Farmer, S. R., and Collins, S. (2001). CCAAT/enhancer-binding protein is required for transcription of the 3-adrenergic receptor gene during adipogenesis. J. Biol. Chem. 276: 722-728. 11024036

Dobens, L. L., Jr. and Bouyain, S. (2012). Developmental roles of tribbles protein family members. Dev Dyn 241: 1239-1248. PubMed ID: 22711497

Engelman, J. A., Lisanti, M. P. and Scherer, P. E. (1998). Specific inhibitors of p38 mitogen-activated protein kinase block 3T3-L1 adipogenesis. J. Biol. Chem. 273(48): 32111-20

Falvey, E., Marcacci, L. and Schibler. U. (1996). DNA-binding specificity of PAR and C/EBP leucine zipper proteins: a single amino acid substitution in the C/EBP DNA-binding domain confers PAR-like specificity to C/EBP. Biol. Chem. 377: 797-809

Gutierrez, S., et al. (2002). CCAAT/enhancer-binding proteins (C/EBP) beta and delta activate osteocalcin gene transcription and synergize with Runx2 at the C/EBP element to regulate bone-specific expression. J. Biol. Chem. 277(2): 1316-23. 11668178

Hegedus, Z., Czibula, A. and Kiss-Toth, E. (2006). Tribbles: novel regulators of cell function; evolutionary aspects. Cell Mol Life Sci 63: 1632-1641. PubMed ID: 16715410

Hegedus, Z., Czibula, A. and Kiss-Toth, E. (2007). Tribbles: a family of kinase-like proteins with potent signalling regulatory function. Cell Signal 19: 238-250. PubMed ID: 16963228

Hemati, N., et al. (1997). Signaling pathways through which insulin regulates CCAAT/enhancer binding protein alpha (C/EBPalpha) phosphorylation and gene expression in 3T3-L1 adipocytes: correlation with glut4 gene expression. J. Biol. Chem. 272(41): 25913-25919

Hua, F., Mu, R., Liu, J., Xue, J., Wang, Z., Lin, H., Yang, H., Chen, X. and Hu, Z. (2011). TRB3 interacts with SMAD3 promoting tumor cell migration and invasion. J Cell Sci 124: 3235-3246. PubMed ID: 21896644

Hwang, C. S., et al. (1996). Transcriptional activation of the mouse obese (ob) gene by CCAAT/enhancer binding protein alpha. Proc. Natl. Acad. Sci. 93: 873-877

Iakova, P., Awad, S. S., and Timchenko, N. A. (2003). Aging reduces proliferative capacities of liver by switching pathways of C/EBPalpha growth arrest. Cell 113: 495-506. 12757710

Jiang, J. G. and Zarnegar, R. (1997). A novel transcriptional regulatory region within the core promoter of the hepatocyte growth factor gene is responsible for its inducibility by cytokines via the C/EBP family of transcription factors. Mol. Cell. Biol.17(10): 5758-5770

Jin, W., et al. (2006). Schnurri-2 controls BMP-dependent adipogenesis via interaction with Smad proteins. Dev. Cell 10(4): 461-71. 16580992

Jones, P. L., Ping, D. and Boss, J. M. (1997). Tumor necrosis factor alpha and interleukin-1beta regulate the murine manganese superoxide dismutase gene through a complex intronic enhancer involving C/EBP-beta and NF-kappaB. Mol. Cell. Biol. 17(12): 6970-6981.

Kawai, S., Kato, T., Sato, M. and Amano, A. (2006). Odd-skipped related 2 gene transcription is regulated by CCAAT enhancer-binding protein delta in mesenchymal C3H10T1/2 cells. Genes Cells 11(2): 163-75. 16436053

Keeshan, K., et al. (2003). Transcription activation function of C/EBPalpha is required for induction of granulocytic differentiation. Blood 102: 1267-1275. 12702500

Keeshan, K., He, Y., Wouters, B. J., Shestova, O., Xu, L., Sai, H., Rodriguez, C. G., Maillard, I., Tobias, J. W., Valk, P., Carroll, M., Aster, J. C., Delwel, R. and Pear, W. S. (2006). Tribbles homolog 2 inactivates C/EBPalpha and causes acute myelogenous leukemia. Cancer Cell 10: 401-411. PubMed ID: 17097562

Keeshan, K., Shestova, O., Ussin, L. and Pear, W. S. (2008). Tribbles homolog 2 (Trib2) and HoxA9 cooperate to accelerate acute myelogenous leukemia. Blood Cells Mol Dis 40: 119-121. PubMed ID: 17988908

Keeshan, K., Bailis, W., Dedhia, P. H., Vega, M. E., Shestova, O., Xu, L., Toscano, K., Uljon, S. N., Blacklow, S. C. and Pear, W. S. (2010). Transformation by Tribbles homolog 2 (Trib2) requires both the Trib2 kinase domain and COP1 binding. Blood 116: 4948-4957. PubMed ID: 20805362

Khanna-Gupta, A., et al. (2001). C/EBPepsilon mediates myeloid differentiation and is regulated by the CCAAT displacement protein (CDP/cut). Proc. Natl. Acad. Sci. 98: 8000-8005. 11438745

Lamb, J., et al. (2003). A mechanism of Cyclin D1 action encoded in the patterns of gene expression in human cancer. Cell 114: 323-334. 12914697

Lee, T., Feig, L. and Montell, D. J. (1996). Two distinct roles for Ras in a developmentally regulated cell migration. Development 122: 409-418

Lee, T., and Montell, D. J. (1997). Multiple Ras signals pattern the Drosophila ovarian follicle cells. Dev. Biol. 185: 25-33

Lee, Y.-H., et al. (1997a). The ability of C/EBPbeta but not C/EBPalpha to synergize with an SP1 protein is specified by the leucine zipper and activation domain. Mol. Cell. Biol. 17: 2038-47

Lee, Y. H., et al. (1997b). Disruption of the c/ebp alpha gene in adult mouse liver. Mol. Cell. Biol. 17(10): 6014-6022

Levine, B., et al. (2007). Notch signaling links interactions between the C/EBP homolog slow border cells and the GILZ homolog bunched during cell migration. Dev. Biol. 305: 217-231. PubMed citation: 17383627

Linhart, H. G., et al. (2001). C/EBPalpha is required for differentiation of white, but not brown, adipose tissue. Proc. Natl. Acad. Sci. 98(22): 12532-7. 11606718

Liu, J. and Farmer, S. R. (2004). Regulating the balance between peroxisome proliferator-activated receptor gamma and ß-catenin signaling during adipogenesis. A glycogen synthase kinase 3ß phosphorylation-defective mutant of ß-catenin inhibits expression of a subset of adipogenic genes. J Biol Chem. 279(43): 45020-7. 15308623

Liu, Y. and Montell, D. J. (2001). jing: a downstream target of slbo required for developmental control of border cell migration Development 128: 321-330. 11152631

Lu, M., Seufert, J. and Habener, J. F. (1997). Pancreatic beta-cell-specific repression of insulin gene transcription by CCAAT/Enhancer-binding protein beta. inhibitory interactions with basic helix-loop-helix transcription factor e47. J. Biol. Chem. 272(45): 28349-28359

Martin, K. A., et al. (1997). A competitive mechanism of CArG element regulation by YY1 and SRF: implications for assessment of Phox1/MHox transcription factor interactions at CArG elements. DNA Cell Biol. 16(5): 653-661

Martin, M. D., et al. (1998). Repeated pulses of serotonin required for long-term facilitation activate mitogen-activated protein kinase in sensory neurons of aplysia. Proc. Natl. Acad. Sci. 95(4): 1864-1869

Masoner, V., Das, R., Pence, L., Anand, G., LaFerriere, H., Zars, T., Bouyain, S. and Dobens, L. L. (2013). The kinase domain of Drosophila Tribbles is required for turnover of fly C/EBP during cell migration. Dev Biol 375: 33-44. PubMed ID: 23305818

Maytin, E. V., et al. (1999). Keratin 10 gene expression during differentiation of mouse epidermis requires transcription factors C/EBP and AP-2. Dev. Biol. 216(1): 164-81. 10588870

Ménard, C., et al. (2002). An essential role for a MEK-C/EBP pathway during growth factor-regulated cortical neurogenesis. Neuron 36: 597-610. 12441050

Melani, M., Simpson, K. J., Brugge, J. S. and Montell, D. (2008). Regulation of cell adhesion and collective cell migration by hindsight and its human homolog RREB1. Curr. Biol. 18(7): 532-7. PubMed Citation: 18394891

Meruvu, S., Hugendubler, L. and Mueller, E. (2011). Regulation of adipocyte differentiation by the zinc finger protein ZNF638. J. Biol. Chem. J. Biol. Chem. 286(30): 26516-23. PubMed Citation: 21602272

Miniaci, M. C., et al. (2008). Sustained CPEB-dependent local protein synthesis is required to stabilize synaptic growth for persistence of long-term facilitation in Aplysia. Neuron 59: 1024-1036. PubMed Citation: 18817739

Mink, S., Haenig, B. and Klempnauer, K. H. (1997). Interaction and functional collaboration of p300 and C/EBPbeta. Mol. Cell. Biol. 17(11): 6609-6617

Moitra, J. L., Mason, M. M., Olive, M., Krylor, D., Gavrilova, O., Marcus-Samuels, B., Feigenbaum, L., Lee, E., Aoyama, T., Eckhaus, M., et al. (1998). Life without white fat: A transgenic mouse. Genes Dev. 12: 3168-3181. 9784492

Montell, D. J., Rorth, P. and Spradling, A. C. (1992). slow border cells, a locus required for a developmentally regulated cell migration during oogenesis, encodes Drosophila C/EBP. Cell 71: 51-62

Murphy, A. M., et al. (1995). The breathless FGF receptor homolog, a downstream target of Drosophila C/EBP in the developmental control of cell migration. Development 121: 2255-2263

Naiki, T., Saijou, E., Miyaoka, Y., Sekine, K. and Miyajima, A. (2007). TRB2, a mouse Tribbles ortholog, suppresses adipocyte differentiation by inhibiting AKT and C/EBPbeta. J Biol Chem 282: 24075-24082. PubMed ID: 17576771

Nerlov, C., et al. (1998). Distinct C/EBP functions are required for eosinophil lineage commitment and maturation. Genes Dev. 12(15): 2413-2423

Niehof, M., Manns, M. P. and Trautwein, C. (1997). CREB controls LAP/C/EBP beta transcription. Mol. Cell. Biol. (7): 3600-3613

Pabst, T., et al. (2001). Dominant-negative mutations of C/EBPA, encoding CCAAT/enhancer binding protein-alpha (C/EBPalpha), in acute myeloid leukemia. Nat. Genet. 27: 263-270. 11242107

Park, B. H., Qiang, L. and Farmer, S. R. (2004). Phosphorylation of C/EBPbeta at a consensus extracellular signal-regulated kinase/glycogen synthase kinase 3 site is required for the induction of adiponectin gene expression during the differentiation of mouse fibroblasts into adipocytes. Mol. Cell Biol. 24(19): 8671-80. 15367685

Pedersen, T. A., et al. (2001). Cooperation between C/EBPalpha, TBP/TFIIB and SWI/SNF recruiting domains is required for adipocyte differentiation. Genes Dev. 15: 3208-3216. 11731483

Petrovick, M. S., et al. (1998). Multiple functional domains of AML1: PU.1 and C/EBPalpha synergize with different regions of AML1. Mol. Cell. Biol. 18(7): 3915-3925

Piontkewitz, Y., Enerbäck, S. and Hedin, L. (1996). Expression of CCAAT Enhancer binding protein-alpha (C/EBP alpha) in the rat ovary: implications for follicular development and ovulation. Dev. Biol. 179: 288-296

Porse, B. T., et al. (2001). E2F repression by C/EBPalpha is required for adipogenesis and granulopoiesis in vivo. Cell 107: 247-258. 11672531

Ross, S. E., et al. (2004). Phosphorylation of C/EBPalpha inhibits granulopoiesis. Mol. Cell. Biol. 24(2): 675-86. 14701740

Robinson, G. W., et al. (1998). The C/EBPbeta transcription factor regulates epithelial cell proliferation and differentiation in the mammary gland. Genes Dev. 12(12): 1907-1916

Radomska, H. S., et al. (1998). CCAAT/enhancer binding protein alpha is a regulatory switch sufficient for induction of granulocytic development from bipotential myeloid progenitors. Mol. Cell. Biol. 18(7): 4301-4314

Reinhart, A. J., et al. (1999). SF-1 (steroidogenic factor-1) and C/EBP beta (CCAAT/enhancer binding protein-beta) cooperate to regulate the murine StAR (steroidogenic acute regulatory) promoter. Mol. Endocrinol. 13(5): 729-41

Rochford, J. J., et al. (2004). ETO/MTG8 is an inhibitor of C/EBPbeta activity and a regulator of early adipogenesis. Mol. Cell. Biol. 24(22): 9863-72. 15509789

Rorth, P., and Montell, D. J. (1992). Drosophila C/EBP: a tissue-specific DNA-binding protein required for embryonic development. Genes Dev. 6: 2299-311

Rorth, P. (1994). Specification of C/EBP function during Drosophila development by the bZIP basic region. Science 266: 1878-1881

Rørth, P., Szabo, K. and Texido, G. (2000). The level of C/EBP protein is critical for cell migration during Drosophila oogenesis and is tightly controlled by regulated degradation. Molec. Cell 6: 23-30

Rosen, E. D., et al. (2002). C/EBPalpha induces adipogenesis through PPARgamma: a unified pathway. Genes Dev. 16: 22-26. 11782441

Saka, Y. and Smith, J. C. (2004). A Xenopus tribbles orthologue is required for the progression of mitosis and for development of the nervous system. Dev Biol 273: 210-225. PubMed ID: 15328008

Scott, L. M., et al. (1992). A novel temporal expression pattern of three C/EBP family members in differentiating myelomonocytic cells. Blood 80 (7): 1725-173

Seagroves, T. N., et al. (1998). C/EBPbeta, but not C/EBPalpha, is essential for ductal morphogenesis, lobuloalveolar proliferation, and functional differentiation in the mouse mammary gland. Genes Dev. 12(12): 1917-1928

Sealy, L., Malone, D. and Pawlak, M. (1997). Regulation of the cfos Serum Response Element by C/EBP beta. Mol. Cell. Biol. 17: 1744-55

Sepulveda, J. L., et al. (1998). GATA-4 and Nkx-2.5 coactivate Nkx-2 DNA binding targets: role for regulating early cardiac gene expression. Mol. Cell. Biol. 18(6): 3405-3415

Shao, D. and Lazar, M. A. (1997). Peroxisome proliferator activated receptor gamma, CCAAT/enhancer-binding protein alpha, and cell cycle status regulate the commitment to adipocyte differentiation. J. Biol. Chem. 272(34): 21473-21478

Shi, X., et al. (2003). A glucocorticoid-induced leucine-zipper protein, GILZ, inhibits adipogenesis of mesenchymal cells. EMBO Rep. 4(4): 374-80. PubMed citation: 12671681

Shimomura, I., Hammer, R. E., Richardson, J. A., Ikemoto, S., Bashmakow, Y., Goldsten, J. L., and Brown, M. S. (1998). Insulin resistance and diabetes mellitus in transgenic mice expressing nuclear SREBP-1c in adipose tissue: Model for congential generalized lipodystrophy. Genes Dev. 12: 3182-3194. 9784493

Sharina, I. G., Martin, E., Thomas, A., Uray, K. L. and Murad, F. (2003). CCAAT-binding factor regulates expression of the beta1 subunit of soluble guanylyl cyclase gene in the BE2 human neuroblastoma cell line. Proc. Natl. Acad. Sci. 100: 11523-11528. Medline abstract: 14504408

Si, K., et al. (2003). A neuronal isoform of CPEB regulates local protein synthesis and stabilizes synapse-specific long-term facilitation in Aplysia. Cell 115: 893-904. PubMed Citation: 14697206

Silver, D. L. and Montell, D. J. (2001). Paracrine signaling through the JAK/STAT pathway activates invasive behavior of ovarian epithelial cells in Drosophila. Cell 107: 831-841. 11779460

Somogyi, K and Rørth, P. (2004). Evidence for tension-based regulation of Drosophila MAL and SRF during invasive cell migration. Dev. Cell 7: 85-93. 15239956

Soriano, H. E., et al. (1998). Lack of C/EBPalpha gene expression results in increased DNA synthesis and in an increased frequency of immortalization of freshly isolated rat hepatocytes. Hepatology 27: 392-40. 9462636

Starz-Gaiano, M., et al. (2008). Feedback inhibition of JAK/STAT signaling by Apontic is required to limit an invasive cell population. Dev. Cell 14: 726-738. PubMed Citation: 18477455

Sterneck, E., Tessarollo, L. and Johnson, P. F. (1997). An essential role for C/EBPbeta in female reproduction. Genes Dev. 11(17): 2153-2162

Tahirov, T. H., et al. (2002). Mechanism of c-Myb-C/EBPß cooperation from separated sites on a promoter. Cell 108: 57-70. 11792321

Tanaka, T., et al. (1997). Defective adipocyte differentiation in mice lacking the C/EBPbeta and/or C/EBPdelta gene. EMBO J. 16(24): 7432-7443

Tang, Q. Q., Jiang, M. S. and Lane, M. D. (1997). Repression of transcription mediated by dual elements in the CCAAT/enhancer binding protein alpha gene. Proc. Natl. Acad. Sci. 94(25): 13571-13575

Thangaraju, M., et al. (2005). C/EBPdelta is a crucial regulator of pro-apoptotic gene expression during mammary gland involution. Development 132: 4675-4685. 16192306

Timchenko, L. T., et al. (2002). Calreticulin interacts with C/EBPalpha and C/EBPbeta mRNAs and represses translation of C/EBP proteins. Mol. Cell. Biol. 22(20): 7242-57. 12242300

Timchenko, N. A., et al. (1997). CCAAT/enhancer binding protein alpha regulates p21 protein and hepatocyte proliferation in newborn mice. Mol. Cell. Biol. 17(12): 7353-7361

Timchenko, N. A., Wilde, M., and Darlington, G. J. (1999). C/EBP alpha regulates formation of S-phase-specific E2F-p107 complexes in livers of newborn mice. Mol. Cell. Biol. 19: 2936-2945. 10082561

Wang, H., Iakova, P., Wilde, M., Welm, A., Goode, T., Roesler, W. J., and Timchenko, N. A. (2001). C/EBPalpha arrests cell proliferation through direct inhibition of cdk2 and cdk4. Mol. Cell 8: 817-828. 11684017

Wang, H., Goode, T., Iakova, P., Albrecht, J., and Timchenko, N. A. (2002). C/EBPalpha triggers proteasome-dependent degradation of cdk4 during growth arrest. EMBO J. 21: 930-941. 11867521

Wang, Q.-F., Cleaves, R., Kummalue, T., Nerlov, C., and Friedman, A. D. (2003). Cell cycle inhibition mediated by the outer surface of the C/EBPalpha basic region is required but not sufficient for granulopoiesis. Oncogene 22: 2548-2255. 12730669

Wang, G.-L., et al. (2004). Liver tumors escape negative control of proliferation via PI3K/Akt-mediated block of C/EBPalpha growth inhibitory activity. Genes Dev. 18: 912-925. 15107404

Wang, H., et al. (2001). C/EBPalpha arrests cell proliferation through direct inhibition of Cdk2 and Cdk4. Molec. Cell 8: 817-828. 11684017

Wang, N. D., et al. (1995). Impaired energy homeostasis in C/EBP alpha knockout mice. Science 269: 1108-1112

Wang, X. Z., et al. (1998). Identification of novel stress-induced genes downstream of chop. EMBO J. 17(13): 3619-30

Wang, X., et al. (2006). Analysis of cell migration using whole-genome expression profiling of migratory cells in the Drosophila ovary. Dev. Cell 10: 483-495. 16580993

Welm, A. L., Timchenko, N. A. and Darlington, G. J. (1999). C/EBPalpha regulates generation of C/EBPbeta isoforms through activation of specific proteolytic cleavage. Mol. Cell. Biol. 19(3): 1695-704. PubMed Citation: 10022857

Yamamoto, M., Uematsu, S., Okamoto, T., Matsuura, Y., Sato, S., Kumar, H., Satoh, T., Saitoh, T., Takeda, K., Ishii, K. J., Takeuchi, O., Kawai, T. and Akira, S. (2007). Enhanced TLR-mediated NF-IL6 dependent gene expression by Trib1 deficiency. J Exp Med 204: 2233-2239. PubMed ID: 17724128

Yamamoto, N., et al. (1999). Activation and degradation of the transcription factor C/EBP during long-term facilitation in Aplysia. J. Neurochem. 73(6): 2415-23. PubMed Citation: 10582601

Yan, D., Wu, Z., Chisholm, A. D. and Jin, Y. (2009). The DLK-1 kinase promotes mRNA stability and local translation in C. elegans synapses and axon regeneration. Cell 138(5): 1005-18. PubMed Citation: 19737525

Yubero, P., et al. (1994). CCAAT/enhancer binding proteins alpha and beta are transcriptional activators of the brown fat uncoupling protein gene promoter. Biochem Biophys Res Commun 198: 653-9

Zafarana, G., et al. (2000). Erythroid overexpression of C/EBPgamma in transgenic mice affects gamma-globin expression and fetal liver erythropoiesis. EMBO J. 19(21): 5856-63.

Zagariya, A., et al. (1998). Tumor necrosis factor alpha gene regulation: enhancement of C/EBPbeta-induced activation by c-Jun. Mol. Cell. Biol. 8(5): 2815-2824

Zhang, J. W., Tang, Q. Q., Vinson, C. and Lane, M. D. (2004). Dominant-negative C/EBP disrupts mitotic clonal expansion and differentiation of 3T3-L1 preadipocytes. Proc. Natl. Acad. Sci. 101(1): 43-7. 14688407

Zhuang, D., Qiu, Y., Kogan, S. C. and Dong, F. (2006). Increased CCAAT enhancer-binding protein epsilon (C/EBPepsilon) expression and premature apoptosis in myeloid cells expressing Gfi-1 N382S mutant associated with severe congenital neutropenia. J. Biol. Chem. 281(16): 10745-51. 16500901

slow border cells: Biological Overview | Evolutionary Homologs | Regulation | Developmental Biology | Effects of Mutation

date revised: 15 July 2013 

Home page: The Interactive Fly © 1997 Thomas B. Brody, Ph.D.

The Interactive Fly resides on the
Society for Developmental Biology's Web server.