hairy

DEVELOPMENTAL BIOLOGY

Embryonic

The Hairy and Even-skipped protein stripes overlap extensively, but are out of phase. hairy expression extends about three cells anterior to the first (most anterior) Eve stripe, two cells anterior to the second Eve stripe, and one cell anterior to the third Eve stripe. It appears to coincide with the fourth Eve stripe (Carroll, 1988).

Expression of hairy can be detected in the stomatogastric nervous system (SNS). It is expressed already in a well defined mitotic domain at stage 5 and continues to be expressed in the SNS anlage through SNS invaginations until the time that vesicles pinch off from the epithelium. Embryos homozygous for a specific P-element insertion in hairy have extra neural cells in the ganglia of the SNS and correspondingly broader fascicles as a result. There is no pair rule phenotype resulting from the specific P-element insertion which must be due to a fortuitous hit of the P-element, affecting only the function of the gene required for neural development. As a result the role of hairy in neural development can be perceived without interference of secondary traits stemming from the pair rule requirements. Thus Hairy is thought to act as a global regulator in restricting achaete expression in proneural clusters (Forjanic, 1997).

Larval

hairy is transiently expressed in a line of cells anterior to the morphogenetic furrow as it traverses the eye disc. Both Hairy and Extramachrochaete negatively regulate the progression of the morphogenetic furrow in the developing eye (Brown, 1995).

Effects of Mutation or Deletion

Mutations that disrupt early hairy activity cause a depression of ftz expression in regions where ftz is not normally expressed. Later in development, hairy is required to suppress ectopic bristle formation on many parts of the adult body (Carroll, 1989).

It has been demonstrated that C-terminal binding protein is essential for proper embryonic segmentation by analyzing embryos lacking maternal CtBP activity. While hairy is probably not the only segmentation gene interacting with CtBP, dose-sensitive genetic interactions exist between CtBP and hairy mutations. h mutations result in a range of cuticle phenotypes from loss or fusion of adjacent denticle bands to a fusion of most of the segments ('lawn' phenotype), with the most common phenotype called the classic pair-rule phenotype that results from the loss of alternating segment-wide regions. Larvae homozygous for a strong h allele, h^7H, display the extreme 'lawn' phenotype, whereas larvae trans-heterozygous for the h^7H allele and a weaker h allele, h^12C, display the classic pair-rule phenotype. This h^7H/h^12C allelic combination was initially used to examine if reducing the CtBP dose maternally would suppress or enhance the intermediate pair-rule phenotype. P1590 was genetically recombined onto a chromosome containing the h^7H allele. Reducing the dose of CtBP maternally results in the suppression of the h^7H/h^12C mutant cuticle phenotype. Likewise, reducing the dose of CtBP maternally in the severe h^7H background suppresses the extreme lawn phenotype. No alterations in viability or phenotype of any progeny classes are observed when P1590 is trans-heterozygous with h^7H, or when the h^7H P1590 recombinant chromosome is crossed to wild-type (Poortinga, 1998).

The magnitude of segregating variation for bristle number in Drosophila exceeds that predicted from models of mutation-selection balance. To evaluate the hypothesis that genotype-environment interaction (GEI) maintains variation for bristle number in nature, the extent of GEI was quantitated for abdominal and sternopleural bristles among 98 recombinant inbred lines, derived from two homozygous laboratory strains, in three temperature environments. There is considerable GEI for both bristle traits. A genome-wide screen was conducted for quantitative trait loci (QTLs) affecting bristle number in each sex and temperature environment, using a dense (3.2-cM) marker map of polymorphic insertion sites of roo transposable elements. Nine sternopleural and 11 abdominal bristle number QTLs were detected. Significant GEI is exhibited by 14 QTLs, but there was heterogeneity among QTLs in their sensitivity to thermal and sexual environments. To further evaluate the hypothesis that GEI maintains variation for bristle number, estimates of allelic effects across environments at genetic loci affecting the traits are required. This level of resolution may be achievable for Drosophila bristle number because candidate loci affecting bristle development often map to the same location as bristle number QTL, including achaete-scute, scabrous, hairy, and Delta (Gurganus, 1998).

naked cuticle (nkd) loss-of-function clones were induced in imaginal discs and adult structures using two strong nkd alleles, nkd^7H16 and nkd^7E89, and one moderately severe allele, nkd^9G33, all of which are embryonic lethal. nkd alleles were originally generated in the genetic background of a weak allele of the pair-rule gene hairy (h¹). h¹ clones give rise to ectopic wing-vein bristles and thoracic microchaetes. Furthermore, nkd and h genetically interact: nkd, h¹/h^null is lethal, whereas h¹/h ^null is viable (A. Martinez-Arias, personal communication to Zeng, 2000). Therefore clones were generated of the strong allele nkd^7E89 from which h¹ had been removed. In many tissues where Wg signals control pattern, including the wing, thorax, abdomen, haltere and eye, phenotypically normal nkd clones are seen. h ¹, nkd^7H16, but not h ⁺, nkd^7E89 or h¹, nkd^9G33 clones give rise to a rough eye phenotype and loss of wing margin bristle phenotype that may be due to h-nkd interactions (Zeng, 2000).

Advances in medicine, agriculture, and an understanding of evolution depend on resolving the genetic architecture of quantitative traits, which is challenging since variation for complex traits is caused by multiple interacting quantitative trait loci (QTL) with small and conditional effects. hairy (h) is a QTL for Drosophila sternopleural bristle number, a model quantitative trait. Near-isoallelic lines (NIL) for the h gene region exhibit significant variation in bristle number and fail to complement a hairy mutation. Sequencing 10 h alleles from a single population has revealed 330 polymorphic sites in ~10 kb. Genotypes for 25 of these and 14 additional sites in the flanking regions were determined for the 57 NIL and associated with variation in bristle number in four genetic backgrounds. A highly significant association was found for a complicated insertion/deletion polymorphism upstream of the transcription start site. This polymorphism, present in 17.5% of the h alleles, was associated with an increase of 0.5 bristle and accounted for 31% of the genetic variance in bristle number in the NIL (Robin, 2002).

The insertion 2187in is a complicated insertion/SNP present in 17.5% of the alleles, where the common sequence ATAAAAAAA has been replaced by TATACATAGTATAGTATATATAGT. Comparison with D. simulans shows that the common sequence is the ancestral state. The presence of 2187in is associated with an increase of 0.64 sternopleural bristles across all genetic backgrounds, with no significant interactions with genetic background or sex. Differences of 0.54, 0.51, and 0.42 bristle between the in2187 and del2187 (the common sequence) alleles are significant in the homozygous NIL, NIL/h¹, and NIL/Sam genotypes, respectively; but a difference of 1.14 bristle was not significant in the chromosome 3 substitution lines. The fraction of the among-line genetic variance associated with del2187in is given by the ratio of the variance component attributable to this marker to the total among-line genetic variance for each genotype and ranged from 12% in the chromosome 3 substitution lines to 73% in the NIL/Sam heterozygotes (Robin, 2002).

It is illustrative to calculate the potential contribution of del2187in to naturally occurring variation in sternopleural bristle number in a random breeding population. This locus would account for only 1.3% of the additive genetic variance and 0.45% of the phenotypic variance. However, an additive model may not be appropriate, since in2187 appears to be dominant to del2187 (Robin, 2002).

The data illustrate how critical it is to utilize the correct density of markers, relative to historical recombination, in association study designs. In outbred populations, the power to detect associations between polymorphic molecular markers and quantitative trait phenotypes depends on the magnitude of the effect of the causal molecular variant [the quantitative trait nucleotide (QTN)], the sample size, and the strength of linkage disequilibrium between the QTN and the markers used in the association test. If the genotype of del2187in had not been determined in this sample, none of the associations would have reached the stringent level of statistical significance required to account for multiple tests. It follows that additional QTN affecting bristle number might have been revealed had the marker density been greater. Resolving which polymorphic site(s) causes variation in phenotypes will ultimately require genotyping all variable sites on large samples of alleles, to eliminate the possibility of hidden causal QTN and to detect informative recombinants. In Drosophila regions of high recombination and polymorphism, this requirement currently restricts the utility of linkage disequilibrium mapping in outbred populations to mapping QTN within candidate genes. While h was a clear candidate gene affecting bristle number, many QTL map to regions containing no obvious candidate genes. With the ultimate availability of stocks containing targeted disruptions of all known and predicted genes in Drosophila and other model organisms, quantitative complementation of QTL alleles to mutations of all genes in the region to which QTL map provides a reliable, rapid, and cost-effective method for nominating candidate genes for further study (Robin, 2002).

This is one of a growing number of examples indicating that variation in noncoding regions is likely to be responsible for quantitative genetic variation, which in turn can motivate functional studies to define regulatory motifs (in this case, regulatory sites for expression of h in the PNS). Intermediate frequency polymorphisms associated with quantitative traits are not likely to be maintained by mutation-selection balance, further motivating large-scale future studies with new designs to detect hallmarks of positive or balancing selection at this locus (Robin, 2002).

Formation of tubes of the correct size and shape is essential for viability of most organisms, yet little is understood of the mechanisms controlling tube morphology. A new allele of hairy has been identified in a mutagenesis screen. hairy mutations cause branching and bulging of the normally unbranched salivary tube, in part through prolonged expression of huckebein (hkb). Hkb controls polarized cell shape change and apical membrane growth during salivary cell invagination via two downstream target genes, crumbs (crb), a determinant of the apical membrane, and klarsicht (klar), which mediates microtubule-dependent organelle transport. In invaginating salivary cells, crb and klar mediate growth and delivery of apical membrane, respectively, thus regulating the size and shape of the salivary tube (Myat, 2002).

Traditional screens aiming at identifying genes regulating development have relied on mutagenesis. A new gene has been identified involved in bristle development, identified through the use of natural variation and selection. Drosophila melanogaster bears a pattern of 11 macrochaetes per heminotum. From a population initially sampled in Marrakech, a strain was selected for an increased number of thoracic macrochaetes. Using recombination and single nucleotide polymorphisms, the factor responsible was mapped to a single locus on the third chromosome, poils au dos (French for 'hairy back'), that encodes a zinc-finger-ZAD protein. The original, as well as new, presumed null alleles of poils au dos are associated with ectopic achaete-scute expression that results in the additional bristles. This suggests a possible role for Poils au dos as a repressor of achaete and scute. Ectopic expression appears to be independent of the activity of known cis-regulatory enhancer sequences at the achaete–scute complex that mediate activation at specific sites on the notum. The target sequences for Poils au dos activity were mapped to a 14 kb region around scute. In addition, pad has been shown to interact synergistically with the repressor hairy and with Dpp signaling in posterior and anterior regions of the notum, respectively (Gibert, 2005).

The generalized increase in ac-sc expression in pad mutants suggests that pad is involved in the repression of ac-sc. Interactions between pad and other known repressors of ac-sc were tested. pad¹ interacts moderately with emc^pel and very strongly with hairy¹. In h¹ homozygotes grown at 18°C, ectopic bristles are occasionally found anterior to the aDC, whereas none were seen at 25°C. In h¹ pad¹ homozygotes, many ectopic bristles were observed at 25°C at positions where none were seen in either of the single mutants. These include DC bristles closer to the thoracic midline and additional bristles between the anterior and posterior scutellars. Interestingly, most of these ectopic bristles are located in the posterior half of the notum whereas the visible effect of pad alone is in the anterior part of the notum (Gibert, 2005).

Alper, S. and Kenyon, C. (2001). REF-1, a protein with two bHLH domains, alters the pattern of cell fusion in C. elegans by regulating Hox protein activity. Development 128(10): 1793-804. 11311160

Androutsellis-Theotokis, A., Leker, R. R., Soldner, F., Hoeppner, D. J., Ravin, R., Poser, S. W., Rueger, M. A., Bae, S. K., Kittappa, R., and McKay, R. D. (2006). Notch signalling regulates stem cell numbers in vitro and in vivo. Nature 442: 823-826. Medline abstract: 16799564

Aronson, B. D., et al. (1997). Groucho-dependent and -independent repression activities of Runt domain proteins. Mol. Cell. Biol. 17(9): 5581-5587.

Barolo, S. and Levine, M. (1997). hairy mediates dominant repression in the Drosophila embryo. EMBO J. 16: 2883-91.

Bae, S.-K., et al. (2000). The bHLH gene Hes6, an inhibitor of Hes1, promotes neuronal differentiation. Development 127: 2933-2943.

Bae, Y.-K., Shimizu, T. and Hibi, M. (2005). Patterning of proneuronal and inter-proneuronal domains by hairy- and enhancer of split-related genes in zebrafish neuroectoderm. Development 132(6): 1375-85.15716337

Bai, G., et al. (2007). Id sustains Hes1 expression to inhibit precocious neurogenesis by releasing negative autoregulation of Hes1. Dev Cell. 13(2): 283-97. PubMed citation: 17681138

Bally-Cuif, L., et al. (2000). Coregulation of anterior and posterior mesendodermal development by a hairy-related transcriptional repressor. Genes Dev. 14: 1664-1677.

Baonza, A. and Freeman, M. (2001). Notch signaling and the initiation of neural development in the Drosophila eye. Development 128: 3889-3898. 11641214

Beatus, P., et al. (1999). The Notch 3 intracellular domain represses Notch 1-mediated activation through Hairy/Enhancer of split (HES) promoters. Development 126: 3925-3935.

Beatus, P., et al. (2001). The origin of the ankyrin repeat region in Notch intracellular domains is critical for regulation of HES promoter activity. Mech. of Dev. 104: 3-20. 11404076

Bessa, J., et al. (2002). Combinatorial control of Drosophila eye development by Eyeless, Homothorax, and Teashirt. Genes Dev. 16: 2415-2427. 12231630

Bessho, Y., et al. (2001). Dynamic expression and essential functions of Hes7 in somite segmentation. Genes Dev. 15: 2642-2647. 11641270

Bessho, Y., et al. (2003). Periodic repression by the bHLH factor Hes7 is an essential mechanism for the somite segmentation clock. Genes Dev. 17: 1451-1456. 12783854

Bianchi-Frias, D., et al. (2004). Hairy transcriptional repression targets and cofactor recruitment in Drosophila. PLoS Biol. 2(7): E178. 15252443

Brown, N.L., Sattler, C.A., Paddock, S.W. and Carroll, S.B. (1995). hairy and emc negatively regulate morphogenetic furrow progresssion in the Drosophila eye. Cell 80: 879-87

Bullock, S. L. and Ish-Horowicz, D. (2001). Conserved signals and machinery for RNA transport in Drosophila oogenesis and embryogenesis. Nature 414(6864): 611-6. 11740552

Bullock, S. L., Zicha, D. and Ish-Horowicz, D., et al. (2003). The Drosophila hairy RNA localization signal modulates the kinetics of cytoplasmic mRNA transport. EMBO J. 22: 2484-2494. 12743042

Bullock, S. L., et al. (2004). Differential cytoplasmic mRNA localisation adjusts pair-rule transcription factor activity to cytoarchitecture in dipteran evolution. Development 131: 4251-4261. 15280214

Carroll, S.B., Laughon, A. and Thallay, B.S. (1988). Expression, function and regulation of the hairy segmentation protein in the Drosophila embryo. Genes Dev. 2: 883-90

Carroll, S.B. and White, J.S. (1989). The role of the hairy gene during Drosophila morphogenesis: stripes in imaginal discs. Genes Dev. 3: 305-316

Cau, E., et al. (2000). Hes genes regulate sequential stages of neurogenesis in the olfactory epithelium. Development 127: 2323-2332.

Chen, H., et al. (1997). Conservation of the Drosophila lateral inhibition pathway in human lung cancer: a hairy-related protein (HES-1) directly represses achaete-scute homolog-1 expression. Proc. Natl. Acad. Sci. 94 (10): 5355-5360.

Cunliffe, V. T. (2004). Histone deacetylase 1 is required to repress Notch target gene expression during zebrafish neurogenesis and to maintain the production of motoneurones in response to hedgehog signalling. Development 131: 2983-2995. 15169759

Damen, W. G. M., Weller, M. and Tautz, D. (2000). Expression patterns of hairy, even-skipped, and runt in the spider Cupiennius salei imply that these genes were segmentation genes in a basal arthropod. Proc. Natl. Acad. Sci. 97: 4515-4519.

Davis, R. L., et al. (2001). Molecular targets of vertebrate segmentation: Two mechanisms control segmental expression of Xenopus hairy2 during somite formation. Dev. Cell 1: 553-565. 11703945

Dawson, S. R., et al. (1995). Specificity for the hairy/enhancer of split basic helix-loop-helix (bHLH) proteins maps outside the bHLH domain and suggests two separable modes of transcriptional repression. Mol. Cell Biol. 15: 6923-6931

Deisseroth, K., et al. (2004). Excitation-neurogenesis coupling in adult neural stem/progenitor cells. Neuron 42: 535-552. 15157417

de la Calle-Mustienes, E., et al. (2002). Xiro homeoproteins coordinate cell cycle exit and primary neuron formation by upregulating neuronal-fate repressors and downregulating the cell-cycle inhibitor XGadd45-gamma. Mech. Dev. 119: 69-80. 12385755

Dréan, B. S.-Le, et al. (1998). Dynamic changes in the functions of Odd-skipped during early Drosophila embryogenesis. Development 125: 4851-4861

Esni, F., et al. (2004). Notch inhibits Ptf1 function and acinar cell differentiation in developing mouse and zebrafish pancreas. Development 131: 4213-4224. 15280211

Feder, J. N., et al. (1994) Genomic cloning and chromosomal localization of HRY, the human homolog to the Drosophila segmentation gene, hairy. Genomics 20: 56-61

Fisher, A. L., Ohsako, S. and Caudy, M. (1996).The WRPW motif of the hairy-related basic helix-loop-helix repressor proteins acts as a 4-amino-acid transcription repression and protein-protein interaction domain. Mol. Cell. Biol. 16: 2670-2677

Forjanic, J. P., et al. (1997). Genetic analysis of stomatogastric nervous system development in Drosophila using enhancer trap lines. Development 186: 139-154.

Fu, W. and Baker, N. E. (2003). Deciphering synergistic and redundant roles of Hedgehog, Decapentaplegic and Delta that drive the wave of differentiation in Drosophila eye development. Development 130: 5229-5239. 12954721

Furukawa, T., et al. (2000). rax, Hes1, and notch1 promote the formation of Müller glia by postnatal retinal progenitor cells. Neuron 26: 383-394.

Gajewski, M., et al. (2003). Anterior and posterior waves of cyclic her1 gene expression are differentially regulated in the presomitic mesoderm of zebrafish. Development 130: 4269-4278. 12900444

Glavic, A., et al. (2004). Interplay between Notch signaling and the homeoprotein Xiro1 is required for neural crest induction in Xenopus embryos. Development 131: 347-359. 14681193

Gao, X., et al. (2001). HES6 acts as a transcriptional repressor in myoblasts and can induce the myogenic differentiation program. J. Cell Biol. 154: 1161-1172. 11551980

Geling, A., et al. (2003). bHLH transcription factor Her5 links patterning to regional inhibition of neurogenesis at the midbrain-hindbrain boundary. Development 130: 1591-1604. 12620984

Geling, A., et al. (2004). Her5 acts as a prepattern factor that blocks neurogenin1 and coe2 expression upstream of Notch to inhibit neurogenesis at the midbrain-hindbrain boundary. Development 131: 1993-2006. 15056616

Gibert, J. M., Marcellini, S., David, J. R., Schlotterer, C. and Simpson, P. (2005). A major bristle QTL from a selected population of Drosophila uncovers the zinc-finger transcription factor Poils-au-dos, a repressor of achaete-scute. Dev. Biol. 288(1): 194-205. 16216235

Goodfellow, H., KrejcÌ, A., Moshkin, Y., Verrijzer, C. P., Karch, F. and Bray, S. J. (2007). Gene-specific targeting of the histone chaperone asf1 to mediate silencing. Dev. Cell 13(4): 593-600. PubMed citation: 17925233

Greenwood, S. and Struhl, G. (1999). Progression of the morphogenetic furrow in the Drosophila eye: the roles of Hedgehog, Decapentaplegic and the Raf pathway. Development 126: 5795-5808

Gurganus, M. C., et al. (1998). Genotype-environment interaction at quantitative trait loci affecting sensory bristle number in Drosophila melanogaster. Genetics 149(4): 1883-1898.

Gutjahr, T. Frei, E. and Noll, M. (1993). Complex regulation of early paired expression: initial activation by gap genes and pattern modulation by pair-rule genes. Development 117: 609-23

Hader, T., et al. (1998). Activation of posterior pair-rule stripe expression in response to maternal caudal and zygotic knirps activities. Mech. Dev. 71(1-2): 177-186.

Hans, S., Scheer, N., Ried, I., v. Weizsäcker, E., Blader, P. and Campos-Ortega, J. A. (2004). her3, a zebrafish member of the hairy-E(spl) family, is repressed by Notch signalling. Development 131: 2957-2969. 15169758

Hartmann, C., et al. (1994). A two-step mode of stripe formation in the Drosophila blastoderm requires interactions among primary pair rule genes. Mech Dev 45: 3-13

Hatakeyama, J., et al. (2004). Hes genes regulate size, shape and histogenesis of the nervous system by control of the timing of neural stem cell differentiation. Development 131: 5539-5550. 15496443

Hays, R., et al. (1999). Patterning of Drosophila leg sensory organs through combinatorial signaling by Hedgehog, Decapentaplegic and Wingless. Development 126: 2891-2899.

Henry, C. A., et al. (2002). Two linked hairy/Enhancer of split-related zebrafish genes, her1 and her7, function together to refine alternating somite boundaries. Development 129: 3693-3704. 12117818

Hirata, H., et al. (2001). Hes1 and Hes3 regulate maintenance of the isthmic organizer and development of the mid/hindbrain. EMBO J. 20: 4454-4466. 11500373

Hojo, M., et al. (2000). Glial cell fate specification modulated by the bHLH gene Hes5 in mouse retina. Development 127: 2515-2522.

Holley, S. A., Geisler, R. and Nusslein-Volhard, C. (2000). Control of her1 expression during zebrafish somitogenesis by a Delta-dependent oscillator and an independent wave-front activity. Genes Dev. 14: 1678-1690.

Holley, S. A., et al. (2002). her1 and the notch pathway function within the oscillator mechanism that regulates zebrafish somitogenesis. Development 129: 1175-1183. 11874913

Ishibashi, M., et al. (1994). Persistent expression of helix-loop-helix factor HES-1 prevents mammalian neural differentiation in the central nervous system. EMBO J. 13: 1799-805

Ishibashi, M., et al. (1995). Targeted disruption of mammalian hairy and Enhancer of split homolog-1 (HES-1) leads to up-regulation of neural helix-loop-helix factors, premature neurogenesis, and severe neural tube defects. Genes Dev. 9: 3136-3148

Ishikawa, A., et al. (2004). Mouse Nkd1, a Wnt antagonist, exhibits oscillatory gene expression in the PSM under the control of Notch signaling. Mech. Dev. 121(12): 1443-53. 15511637

Jarriault, S., et al. (1998). Delta-1 activation of Notch-1 signaling results in HES-1 transactivation. Mol. Cell. Biol. 18(12): 7423-7431.

Jiménez, G., Pinchin, S. M. and Ish-Horowicz, D. (1996). In vivo interactions of the Drosophila Hairy and Runt transcriptional repressors with target promoters. EMBO J. 7088-7098

Joshi, M., Buchanan, K. T., Shroff, S. and Orenic, T. V. (2006). Delta and Hairy establish a periodic prepattern that positions sensory bristles in Drosophila legs. Dev. Biol. 293(1): 64-76. 16542648

Jouve, C., et al. (2000). Notch signaling is required for cyclic expression of the hairy-like gene HES1 in the presomitic mesoderm. Development 127: 1421-1429.

Ju, B. G., et al. (2004). Activating the PARP-1 sensor component of the Groucho/ TLE1 corepressor complex mediates a CaMKinase II-dependent neurogenic gene activation pathway. Cell 119: 815-829. 15607978

Kawamura, A., Koshida, S., Hijikata, H., Sakaguchi, T., Kondoh, H. and Takada, S. (2005). Zebrafish hairy/enhancer of split protein links FGF signaling to cyclic gene expression in the periodic segmentation of somites. Genes Dev. 19(10): 1156-61. 15905406

Kim, H. K. and Siu, G. (1998). The Notch pathway intermediate HES-1 silences CD4 gene expression. Mol. Cell. Biol. 18(12): 7166-7175.

Kokubo, H., et al. (2005). Mouse hesr1 and hesr2 genes are redundantly required to mediate Notch signaling in the developing cardiovascular system. Dev. Biol. 278: 301-309. 15680351

Kokubo, H., et al. (2007). Hesr1 and Hesr2 regulate atrioventricular boundary formation in the developing heart through the repression of Tbx2. Development 134: 747-755. Medline abstract: 17259303

Kondo, T. and Raff, M. (2000). Basic helix-loop-helix proteins and the timing of oligodendrocyte differentiation. Development 127: 2989-2998.

Koyano-Nakagawa, N., et al. (2000). Hes6 acts in a positive feedback loop with the neurogenins to promote neuronal differentiation. Development 127: 4203-4216

Kwon, C., et al. (2004). Opposing inputs by Hedgehog and Brinker define a stripe of hairy expression in the Drosophila leg imaginal disc. Development 131: 2681-2692. 15128656

Lai, E. and Posakony, J. (1997). The Bearded box, a novel 3' UTR sequence motif, mediates negative post-transcriptional regulation of Bearded and Enhancer of split Complex gene expression. Development 124(23): 4847-4856

Lamar, E. and Kintner, C. (2005). The Notch targets Esr1 and Esr10 are differentially regulated in Xenopus neural precursors. Development 132(16): 3619-30. 16077089

Langeland, J. A., et al. (1994). Positioning adjacent pair-rule stripes in the posterior Drosophila embryo. Development 120: 2945-2955

La Rosee, A., et al. (1997). Mechanism and Bicoid-dependent control of hairy stripe 7 expression in the posterior region of the Drosophila embryo. EMBO J. 16(14): 4403-4411.

La Rosee-Borggreve, E., et al. (1999). hairy stripe 7 element mediates activation and repression in response to different domains and levels of Kruppel in the Drosophila embryo. Mech. of Dev. 89: 133-140.

Lai, E. C. and Posakony, J. W. (1998). Regulation of Drosophila neurogenesis byRNA:RNA duplexes? Cell 93: 1103-1104

Latimer, A. J., et al. (2002). Delta-Notch signaling induces hypochord development in zebrafish. Development 129: 2555-2563. 12015285

Lobe, C. G. (1997). Expression of the helix-loop-helix factor, Hes3, during embryo development suggests a role in early midbrain-hindbrain patterning. Mech. Dev. 62 (2): 227-237.

Lopez, S. L., et al. (2005). The Notch-target gene hairy2a impedes the involution of notochordal cells by promoting floor plate fates in Xenopus embryos. Development 132(5): 1035-46.15689375

Matter-Sadzinski, L., et al. (2005). A bHLH transcriptional network regulating the specification of retinal ganglion cells. Development 132(17): 3907-21. 16079155

McLarren, K. W., et al. (2000). The mammalian basic helix loop helix protein HES-1 binds to and modulates the transactivating function of the runt-related factor Cbfa1. J. Biol. Chem. 275(1): 530-8.

Minguillón, C., et al. (2003}. The amphioxus Hairy family: differential fate after duplication. Development 130: 5903-5914. 14561632

Müller, M., Weizäcker, E. v. and Campos-Ortega, J. A. (1996). Expression domains of a zebrafish homologue of the Drosophila pair-rule gene hairy corresponding to primordia of alternating somites. Development 122 2071-78

Molloy, D. P., et al. (2001). Structural determinants outside the PXDLS sequence affect the interaction of adenovirus E1A, C-terminal interacting protein and Drosophila repressors with C-terminal binding protein. Biochim. Biophys. Acta. 1546(1): 55-70. 11257508

Morimura, T., Goitsuka, R., Zhang, Y., Saito, I., Reth, M. and Kitamura, D. (2000). Cell cycle arrest and apoptosis induced by Notch1 in B cells. J. Biol. Chem. 275(47): 36523-31. 10967117

Mukhopadhyay, M., et al. (2001). Dickkopf1 is required for embryonic head induction and limb morphogenesis in the mouse. Developmental Cell 1: 423-434

Myat, M. M. and Andrew, D. J. (2002). Epithelial tube morphology is determined by the polarized growth and delivery of apical membrane. Cell 111(6): 879-91. 12526813

Nakagawa, O., et al. (1999). HRT1, HRT2, and HRT3: a new subclass of bHLH transcription factors marking specific cardiac, somitic, and pharyngeal arch segments. Dev. Biol. 216(1): 72-84.

Nam, Y., et al. (2007). Cooperative assembly of higher-order Notch complexes functions as a switch to induce transcription. Proc. Natl. Acad. Sci. 104: 2103-2108. Medline abstract: 17284587

Nambu, P. A. and Nambu, J. R. (1996). The Drosophila fish-hook gene encodes a HMG domain protein essential for segmentation and CNS development. Development 122: 3467-75

Neves, A. and Priess, J. R. (2005). The REF-1 family of bHLH transcription factors pattern C. elegans embryos through Notch-dependent and Notch-independent pathways. Dev. Cell 8(6): 867-79. 15935776

Ninkovic, J., et al. (2005).Inhibition of neurogenesis at the zebrafish midbrain-hindbrain boundary by the combined and dose-dependent activity of a new hairy/E(spl) gene pair. Development 132(1): 75-88.15590746

Niwa, Y., Masamizu, Y., Liu, T., Nakayama, R., Deng, C. X. and Kageyama, R. (2007). The initiation and propagation of Hes7 oscillation are cooperatively regulated by Fgf and notch signaling in the somite segmentation clock. Dev. Cell 13(2): 298-304. PubMed citation: 17681139

Oates, A. C. and Ho, R. K. (2002). Hairy/E(spl)-related (Her) genes are central components of the segmentation oscillator and display redundancy with the Delta/Notch signaling pathway in the formation of anterior segmental boundaries in the zebrafish. Development 129: 2929-2946. 12050140

Ochoa-Espinosa, A., Yucel, G., Kaplan, L., Pare, A., Pura, N., Oberstein, A., Papatsenko, D. and Small S. (2005). The role of binding site cluster strength in Bicoid-dependent patterning in Drosophila. Proc. Natl. Acad. Sci. 102(14): 4960-5. 15793007

Ohsako, S., et al. (1994). Hairy function as a DNA-binding helix-loop-helix repressor of Drosophila sensory organ formation. Genes Dev. 8: 2743-55

Ohtsuka, T., et al. (1999). Hes1 and Hes5 as Notch effectors in mammalian neuronal differentiation. EMBO J. 18(8): 2196-2207

Orenic, T. W., et al. (1993) The spatial organization of epidermal structures: hairy establishes the geometrical pattern of Drosophila leg bristles by delimiting the domains of achaete expression. Development 118: 9-20

Palmeirim, I., et al. (1997). Avian hairy gene expression identifies a molecular clock linked to vertebrate segmentation and somitogenesis. Cell 91(5): 639-648.

Pasini, A., Jiang, Y.-J. and Wilkinson, D. G. (2004). Two zebrafish Notch-dependent hairy/Enhancer-of-split-related genes, her6 and her4, are required to maintain the coordination of cyclic gene expression in the presomitic mesoderm. Development 131: 1529-1541. 15023930

Pinto, M., and Lobe, C. G. (1996). Products of the grg (Groucho-related gene) family can dimerize through the amino-terminal Q domain. J. Biol. Chem. 271: 33026-31

Poortinga, G., Watanabe, M. and Parkhurst, S. M. (1998). Drosophila CtBP: a Hairy-interacting protein required for embryonic segmentation and hairy-mediated transcriptional repression. EMBO J. 17(7): 2067-2078.

Read, D., Levine, M. and Manley, J.L. (1992). Ectopic expression of the Drosophila tramtrack gene results in multiple embryonic defects, including repression of even skipped and fushi tarazu. Mech. Dev. 38(3): 183-95

Robin, C., et al. (2002). hairy: A quantitative trait locus for Drosophila sensory bristle number. Genetics 162: 155-164. 12242230

Rosenberg, M. I. and Parkhurst, S. M. (2002). Drosophila Sir2 is required for heterochromatic silencing and by euchromatic Hairy/E(Spl) bHLH repressors in segmentation and sex determination. Cell 109: 447-458. 12086602

Ross, J. M., Kalis, A. K., Murphy, M. W. and Zarkower, D. (2005). The DM domain protein MAB-3 promotes sex-specific neurogenesis in C. elegans by regulating bHLH proteins. Dev. Cell 8(6): 881-92. 15935777

Rossner, M. J., et al. (1998). SHARPs: mammalian enhancer-of-split- and hairy-related proteins coupled to neuronal stimulation. Mol. Cell. Neurosci. 10(3-4): 460-75.

Rushlow, C.A., et al. (1989). The Drosophila hairy protein acts in both segmentation and bristle patterning and shows homology to N-myc. EMBO J 8: 3095-3103

Russell, S. R. H., et al. (1996). The Dichaete gene of Drosophila melanogaster encodes a SOX-domain protein required for embryonic segmentation. Development 122: 3669-76

Satow, T., et al. (2001). The basic helix-loop-helix gene hesr2 promotes gliogenesis in mouse retina. J. Neurosci. 21(4): 1265-1273. 11160397

Shinga, J., et al. (2001). Early patterning of the prospective midbrain-hindbrain boundary by the HES-related gene XHR1 in Xenopus embryos. Mech. Dev. 109(2): 225-39. 11731236

Sieger, D., Tautz, D. and Gajewski, M. (2003). The role of Suppressor of Hairless in Notch mediated signalling during zebrafish somitogenesis. Mech. Dev. 120: 1083-1094. 14550536

Solecki, D. J., et al. (2001). Activated Notch2 signaling inhibits differentiation of cerebellar granule neuron precursors by maintaining proliferation. Neuron 31: 557-568. 11545715

Sugimori, M., et al. (2007). Combinatorial actions of patterning and HLH transcription factors in the spatiotemporal control of neurogenesis and gliogenesis in the developing spinal cord. Development 134(8): 1617-29. Medline abstract: 17344230

Taelman, V., et al. (2004). Sequences downstream of the bHLH domain of the Xenopus hairy-related transcription factor-1 act as an extended dimerization domain that contributes to the selection of the partners. Dev. Biol. 276(1): 47-63. 15531363

Tallafuß, A. and Bally-Cuif, L. (2003). Tracing of her5 progeny in zebrafish transgenics reveals the dynamics of midbrain-hindbrain neurogenesis and maintenance. Development 130: 4307-4323. 12900448

Tomita, K., et al. (1996). Mammalian hairy and Enhancer of split homolog 1 regulates differentiation of retinal neurons and is essential for eye morphogenesis. Neuron 16: 723-734.

Tomita, K., et al. (1999). The bHLH gene Hes1 is essential for expansion of early T cell precursors. Genes Dev. 13(9): 1203-10.

Tsai, C, and Gergen, J. P. (1994). Gap gene properties of the pair-rule gene runt during Drosophila segmentation. Development 120: 1671-1683

Tsai, C. and Gergen. P. (1995). Pair-rule expression of the Drosophila fushi tarazu gene: a nuclear receptor response element mediates the opposing regulatory effects of runt and hairy. Development 121: 453-462

Tulin, A., Stewart, D. and Spradling, A. C. (2002). The Drosophila heterochromatic gene encoding poly(ADP-ribose) polymerase (PARP) is required to modulate chromatin structure during development. Genes Dev. 16(16): 2108-19. 12183365

Tulin, A. and Spradling, A. (2003). Chromatin loosening by poly(ADP)-ribose polymerase (PARP) at Drosophila puff loci. Science 299: 560-562. 12543974

Umbhauer, M., Boucaut, J.-C. and Shi, D.-L. (2001). Repression of XMyoD expression and myogenesis by Xhairy-1 in Xenopus early embryo. Mech. Dev. 109: 61-68. 11677053

Ursuliak, Z., et al (1997). Differential accumulation of DPTP61F alternative transcripts: regulation of a protein tyrosine phosphatase by segmentation genes. Mech. Dev. 65(1-2): 19-30.

Van Doren, M., et al. (1994). Negative regulation of proneural gene activity: hairy is a direct transcriptional repressor of achaete. Genes Dev. 8: 2729-42

Vasiliauskas, D. and Stern, C. D. (2000). Expression of mouse HES-6, a new member of the Hairy/Enhancer of split family of bHLH transcription factors. Mech. Dev. 98: 133-137.

Vasiliauskas, D., Laufer, E. and Stern, C. D. (2003). A role for hairy1 in regulating chick limb bud growth. Dev. Biol. 262: 94-106. 14512021

Wesley, C. S. (1999). Notch and Wingless regulate expression of cuticle patterning genes. Mol. Cell. Biol. 19: 5743-5758.

Wrischnik, L. A. and Kenyon, C. J. (1997). The role of lin-22, a hairy/enhancer of split homolog, in patterning the peripheral nervous system of C. elegans. Development 124(15): 2875-2888.

Wu, L., et al. (2000). MAML1, a human homologue of Drosophila mastermind, is a transcriptional co-activator for NOTCH receptors. Nat Genet. 26(4): 484-9. 11101851

Yao, J., Lai, E. and Stifani, S. (2001). The winged-helix protein Brain Factor 1 interacts with Groucho and Hes proteins to repress transcription. Mol. Cell. Biol. 21: 1962-1972. 11238932

Yu, Y. and Pick, L. (1995). Non-periodic cues generate seven ftz stripes in the Drosophila embryo. Mech Dev 50: 163-175

Zhang, H. and Levine, M. (1999). Groucho and dCtBP mediate separate pathways of transcriptional repression in the Drosophila embryo. Proc. Natl. Acad. Sci. 96(2): 535-40.

Zeng, W., et al. (2000). naked cuticle encodes an inducible antagonist of Wnt signaling. Nature 403: 789-795.

Zheng, J. L., et al. (2000). Hes1 is a negative regulator of inner ear hair cell differentiation. Development 127: 4551-4560

date revised: 25 July 2008

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

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