Adh transcription factor 1
A monoclonal antibody (MAb Adf1-17) was produced against Adf1 that recognizes a single band of approximately 34 kD on Western blots of head tissue. NoAdf1 expression is detected in embryos 45 min after egg laying, which is before the onset of zygotic transcription. Widespread expression is seen, however, from approximately 2 hr after egg laying onward. These observations support the notion that Adf1 is expressed only in zygotes. At stage 16, wild-type embryos show widespread nuclear expression, with intense staining in the ventral nerve cord (England, 1992 and DeZazzo, 2000). nalP1 homozygotes show significantly reduced levels of Adf1, compared even to heterozygous flies carrying only one copy of Adf1+. In third instar larva, Adf1 expression is widespread in the nervous system. In nalP1 mutants, Adf1 levels appear uniformly reduced in the central brain and ventral ganglia. In adult heads, Adf1 expression is observed only in nuclei throughout the adult brain and with no apparent preferential expression. Here again, Adf1 immunoreactivity is uniformly reduced in homozygous nalP1/nalP1 mutants. Thus, at all developmental stages examined, Adf1 expression appears widespread, quantitatively reduced in mutants, and restricted to the nuclear compartment (DeZazzo, 2000).
In a behavioral screen for olfactory memory mutants, 2182 transposant strains were each assayed for 3 hr memory retention after a single training session of a Pavlovian olfactory conditioning procedure. Four mutant lines displayed lower than normal memory scores and normal perception of the component stimuli: latheo, linotte, golovan, and nalyot (nal). In wild-type flies, a single session of Pavlovian olfactory conditioning produces memory that decays to baseline levels by 24 hr, is insensitive to cycloheximide feeding, and is not disrupted by induced expression of a CREB repressor transgene. Immediately after such training, nal mutants show a mild but significant disruption of conditioned odor avoidance behavior. Thereafter, memory decay (the slope of the forgetting curve) is normal in nal mutants (DeZazzo, 2000).
Despite their performance defect in Pavlovian memory, nal mutants display normal 'task-relevant' sensorimotor responses. Wild-type and mutant flies show similar levels of shock reactivity at the intensity (60V) used for Pavlovian training and at lower intensities. Likewise, wild-type and mutant flies exhibit similar levels of olfactory acuity to the odorants MCH and OCT at the intensity used for Pavlovian training and with a 100-fold dilution. Thus, the performance defect of nal mutants after Pavlovian training cannot be explained by disruptions in the perception of, or responses to, the stimuli presented. Rather, nal mutants appear unable to associate the two stimuli normally when they are presented together (DeZazzo, 2000).
The nalP1 mutation is associated with a single P element (PlacW) insertion at cytological position 42D1-2, located on the proximal right arm of the second chromosome. PlacW encodes a readily scoreable marker, the mini-white eye color gene. This marker was selected against in a standard mating scheme to remobilize the P element used to generate 50 independent excision strains. The excision strains were screened for precise excisions (revertants) to confirm that the nal memory defect is associated with the original P element insertion. By performing PCR on genomic DNA with primers flanking the P insertion site, ten candidate precise excisions were identified. All were homozygous viable. Three were arbitrarily selected for further analysis by PCR cloning and sequencing; all were shown to be molecular revertants. These strains, nalve25A, nalve80, and nalve96, then were tested for memory individually and in heteroallelic combinations with each other. All six genotypes yield normal memory, indicating that the nalP1 P insertion is responsible for the nal memory defect (DeZazzo, 2000).
Of the 50 excision strains, nearly one-third are homozygous lethal, suggesting that the nal P element is linked tightly to an essential locus. Strains with deletions of the P element that extends into the flanking genomic sequences are homozygous lethal and include nalle55 and nalle60. These strains complement the lethal deficiencies Df(2R) cn88b and Df(2R) cn87e, but not Df(2R)42 and Df(2R)nap12. Genomic mapping of nalle55 reveals a deletion extending at least 13 kb to the right of the P element. Mapping of nalle60 reveals two molecular perturbations: (1) a closely linked 1.8 kb deletion in the flanking region and (2) 30 bp of terminal P element sequences along with an 8 bp target site duplication. Mapping of viable excision nalve48 reveals the same 38 bp disruption as that in nalle60 with no discernible disruptions of flanking genomic regions (DeZazzo, 2000).
Memory was examined in strains carrying different combinations of the nalP1, nalle60, nalve48, and nal+ alleles. All three alleles are recessive to the wild-type allele for memory. In heteroallelic combinations, only nalle60/nalP1 flies show a memory deficit. Normal memory for nalve48/nalP1 flies indicates that the failure of nalle60 to complement nalP1 must arise from its 1.8 kb deletion rather than the 38 bp duplication. These results verify that the nalP1 P element insertion disrupts olfactory memory (DeZazzo, 2000).
The nalP1 P element is positioned within the large intron of the Adf1 transcription unit, 147 bp downstream of the splice donor site. This intron disrupts the Adf1 coding region at the predicted junction of two alpha helices that constitutes its signature myb-related helix-turn-helix motif. Construction of the genomic and transcript map also reveals that the nalle60 lesion extends from 351 bp upstream of the terminal exon to 150 bp past the poly(A) site. The nalle60 allele is therefore a null mutation, removing most of the protein (210 amino acids), including essential domains required for DNA binding and transactivation. Given that the lethality of nalle60 comaps to the region, Adf1 is an essential gene. Moreover, the failure of nalP1 to complement nalle60 for memory provides strong genetic evidence that disruptions of Adf1 can affect adult olfactory memory (DeZazzo, 2000).
Since Adf1 is expressed in both the developing and adult animal, inducible transgene technology was used to address Adf1 function in adult behavior. Three independent transgenic strains were isolated expressing the wild-type Adf1 gene under control of the hsp70 promoter. In addition to conferring acute inducibility, the hsp promoter drives constitutive ('leaky') transgene expression. Given the essential nature of Adf1, 'leaky' expression of the Adf1+ transgenes was manipulated by raising the animals at different temperatures. Northern blot analysis of adult head RNA reveals leaky Adf1 transgene expression in nalP1; hsp-Adf1+-11 adults raised continuously at either 18°C or 25°C. Leaky expression of hsp-Adf1+-11 at 18°C or 25°C is sufficient to rescue the lethality of nalle60/nalle55 null mutants. These results confirm the essential role of Adf1 for viability and set the stage for behavioral studies (DeZazzo, 2000).
It was asked whether induced transgene expression can rescue the memory defect of nalP1 mutants. nalP1; hsp-Adf1+-11 adults raised continuously at 18°C show partial behavioral rescue. The same animals show complete rescue when raised at 18°C during development and were then shifted to 25°C for the first 3 days after eclosion. Thus, chronic expression of Adf1+ in adults is sufficient to rescue the nal memory defect. These results suggest that adult expression of Adf1 is required for normal memory (DeZazzo, 2000).
Adf1 expression also has a developmental role. Two lines of investigations support this notion. (1) Temperature-shift experiments of hsp-Adf1+ reveal a deleterious period of overexpression that appears confined to development. When raised at 25°C, olfactory memory in +; hsp-Adf1+-8, -11, and -32 lines (and in nalP1; hsp-Adf1+-11 flies) is lower than normal. When raised at 18°C, however, memory in each line is similar to that in wild-type flies and is not diminished when the 18°C rearing period is followed by a shift to 25°C for 3 days as adults (DeZazzo, 2000).
(2) Acute manipulations of Adf1 expression in adults fail to produce a specific impairment of memory formation. Memory is normal in adult hsp-Adf1+-8;+ animals, when they are raised at 18° to minimize leaky Adf1 expression and then given two 30 min heat shocks (37°C) 24 and 3 hr prior to training. Similarly, a 30 min heat shock (37°C) in nalP1; hsp-Adf1+-11 or hsp-Adf1+-8; nalP1 adults 3 hr before training neither rescues nor worsens their early memory deficits, despite a dramatic induction of the Adf1 protein. Together, these results suggest that regulated Adf1 expression during development is critical for optimal adult memory (DeZazzo, 2000).
To investigate the general role of Adf1 during nervous system development, three independent transgenic strains were generated expressing Adf1+ under control of the UAS promoter. Each strain was crossed to a panel of GAL4 enhancer-trap lines with various patterns of expression in the nervous system: elav-GAL4 and scabrous-GAL4 express widely in the CNS. MZ1580 and C321c express primarily in developing glia. C747, 201Y, 238Y, and OK107 express preferentially in mushroom bodies. Within the central complex, an adult brain structure, OK348, expresses preferentially in the fan-shaped body, and C232, the most specific line of all, expresses with near exclusivity in the ellipsoid body. When the UAS-Adf1+ transgenes are expressed with these GAL4 lines, all fail to survive to adulthood, except for C232/+; UAS-Adf1+/+ flies. The onset of lethality varies from late embryo to late pupa (DeZazzo, 2000).
Together, these observations suggest that the levels of Adf1 must be maintained within a narrow range of expression during development to ensure proper biological function. Such findings are consistent with behavioral investigations, which also reveal a tight dependence of optimal memory upon proper Adf1 expression (DeZazzo, 2000).
Given the inviability of homozygous null mutants, their lethal phase was examined in more detail. About 75% of nalle60/nalle60 mutants die as mature embryos. The remaining 25% hatch and manifest basic behavioral responses, such as forward and backward locomotion to tactile stimuli. These animals are sluggish, however, fail to grow normally, and die before the third instar stage. Mutant nalle55/nalle55 and nalle55/nalle60 flies show a developmental etiology similar to that of nalle60/nalle60 animals. These results suggest an onset of lethality beginning late in embryogenesis and, in some cases, extending into early stages of larval development (DeZazzo, 2000).
In late stage nalle60/nalle60 embryos, development of the CNS, PNS, and trachea appears normal, as does expression of the cell adhesion molecule FAS II (expressed in a subset of PNS and CNS axons), Repo (a nuclear protein expressed in proliferating glia), and the patterning genes Eve and En (which function late in embryogenesis to guide differentiation of a number of cell types, including a subset of neurons). These data suggest unperturbed neuroanatomy during embryogenesis (DeZazzo, 2000).
Two hypomorphic genotypes, nalP1 homozygotes and nalP1/nalle60 mutants, routinely survive to adulthood, thereby permitting an evaluation of gross anatomical structures in the adult brain. The mushroom bodies and central complex, in particular, have been implicated in associative olfactory learning. Visual inspection of frontal sections from wild-type and mutant adult brains reveals no obvious malformations in gross anatomy. For example, the alpha and ß lobes of the mushroom bodies show normal fasciculation and orientation. Likewise, substructures of the central complex appear intact; the fan-shaped body is not split and there is no ventral opening or flattening of the ellipsoid body. A more quantitative 'planimetric' assessment of neuropilar volumes of adult mushroom body calyces and central complex analysis was carried out in wild-type (+), heterozygous (+/nalle60) flies, and hypomorphic mutants (nalP1/nalle60). No significant differences in males or females were found for either anatomical region (DeZazzo, 2000).
The failure of morphological studies to reveal gross defects in the nervous system suggested the value of an examination of Adf1 function at the larval neuromuscular junction (NMJ). At this peripheral synapse, structure can be examined by analyzing the numbers and distributions of variocosities (synaptic boutons), and synaptic function can be analyzed by recording spontaneous and evoked transmitter release onto muscle. Since Adf1 expression is widespread in the larval ventral ganglia and reduced in nalP1 mutants, the NMJ was considered a likely place to quantitate the role of Adf1 in the development of synaptic connections (DeZazzo, 2000).
Synaptic boutons were examined on muscles 6 and 7, which are innervated by the same motor neurons, and a striking correlation between Adf1 expression levels and bouton number was found. When Adf1 expression is reduced (in nalP1 mutants), the number of boutons is significantly reduced. Conversely, when Adf1 expression is greater than normal (in hsp-Adf1+-8 or -11 animals raised at temperatures that produce leaky expression of the transgene), the number of boutons is significantly increased. Opposing changes in Adf1 expression levels, therefore, are correlated with opposing effects on synaptic structure, yielding a difference between these extremes of 30% (DeZazzo, 2000).
Three lines of evidence support the specificity of these observations. (1) The change of synapse number in nalP1 mutants does not appear to arise from a defect in neuronal proliferation. Two motor neurons normally innervate muscle 6, terminating in type 1s and type 1b boutons. Mutant nalP1 and hsp-Adf1+-8 animals show both types of boutons as well as normal levels and distributions of Synaptotagmin within them. (2) The Adf1 null allele, nalle60, fails to complement the bouton defect of nalP1 mutants -- just as it fails to complement the memory defect. (3) Leaky expression of an hsp-Adf1+ transgene is capable of rescuing the bouton defect of nalP1; hsp-Adf1+-11 mutants, just as it is capable of rescuing the memory defect. Collectively, these observations suggest that Adf1 plays a role in postmitotic stages of neuronal development. Given the reciprocal actions of Adf1 on bouton number, this role appears to be at the level of synapse formation and/or maturation (DeZazzo, 2000).
Spontaneous and evoked synaptic transmission were evaluated in wild-type larvae, nalP1 mutants and hsp-Adf1+-8 or hsp-Adf1+-11 transgenic animals. EJC and mEJC amplitudes do not differ among the different genotypes, being approximately 135 and 0.72 nA, respectively. Thus, quantal content, the number of synaptic vesicles released per action potential, is unaffected by these perturbations of Adf1 levels. mEJC frequency also is normal in nal mutant and hsp-Adf1+ transgenic flies. Together, these data support a preferential role for Adf1 in maturation of synaptic structure rather than function (DeZazzo, 2000).
Adf1's widespread expression in the adult brain and its involvement in synapse formation at the NMJ suggest that disruption of this transcription factor might yield a defect in adult long-term memory formation. In essence, long-term memory likely requires increases in both synaptic structure and function. If nal blocks an experience-dependent increase in synaptic structure, then, by analogy to observations at the NMJ, it should block any concomitant increase in synaptic function. In wild-type flies, ten sessions of Pavlovian olfactory conditioning produce two types of long-lasting memory that can be distinguished on the basis of behavioral, genetic, and pharmacological properties. Ten 'massed' training sessions (with no rest interval between sessions) gives rise only to an anesthesia-resistant memory (ARM). ARM decays to baseline within 4 days after training, is immune to inhibitors of protein synthesis, is not disrupted by overexpression of a dominant-negative CREB transgene, and is disrupted in radish mutants. Ten 'spaced' training sessions (with a 15 min rest interval between sessions) gives rise to ARM and a bona fide long-term memory (LTM). LTM persists for at least 7 days, is sensitive to inhibitors of protein synthesis, is disrupted by overexpression of a dominant-negative CREB transgene, is normal in radish mutants, and is induced after only one training session by overexpression of a CREB activator transgene. Thus, LTM appears to be transcription dependent, while ARM does not (DeZazzo, 2000 and references therein).
One day memory retention was quantified in wild-type flies and nalP1 mutants after they were subjected to spaced or massed training in experimenter-blind, balanced experiments replicated over 6 days. At this retention interval, memory after spaced training in wild-type flies (LTM + ARM) is roughly twice that of memory after massed training (ARM only). In nalP1 mutants, 1 day memory after massed training is similar to that of wild-type flies, suggesting that ARM is normal in mutant flies. In contrast, 1 day memory after spaced training in mutant flies is significantly lower than that in wild-type flies and, in fact, is similar to 1 day memory after massed training in wild-type (and mutant) flies. These observations suggest that LTM is absent in nalP1 mutants (DeZazzo, 2000).
To confirm this notion, 7 day memory also was assayed. Significant levels of performance are seen at this retention interval only after spaced training and only with the formation of protein synthesis- and CREB-dependent LTM. No significant 7 day memory was detected in nalP1 flies. Together, these behavioral experiments indicate that LTM is abolished in nal mutants (DeZazzo, 2000).
Dendrite arborization patterns are critical determinants of neuronal function. To explore the basis of transcriptional regulation in dendrite pattern formation, RNA interference (RNAi) was used to screen 730 transcriptional regulators and 78 genes involved in patterning the stereotyped dendritic arbors of class I da neurons were identified in Drosophila. Most of these transcriptional regulators affect dendrite morphology without altering the number of class I dendrite arborization (da) neurons and fall primarily into three groups. Group A genes control both primary dendrite extension and lateral branching, hence the overall dendritic field. Nineteen genes within group A act to increase arborization, whereas 20 other genes restrict dendritic coverage. Group B genes appear to balance dendritic outgrowth and branching. Nineteen group B genes function to promote branching rather than outgrowth, and two others have the opposite effects. Finally, 10 group C genes are critical for the routing of the dendritic arbors of individual class I da neurons. Thus, multiple genetic programs operate to calibrate dendritic coverage, to coordinate the elaboration of primary versus secondary branches, and to lay out these dendritic branches in the proper orientation (Parrish, 2006; Full text of article).
To assay for the stereotyped dendrite arborization pattern of class I da neurons (hereafter referred to as class I neurons) in RNAi-based analysis of dendrite development, a Gal4 enhancer trap line (Gal4221) was used that is highly expressed in class I neurons and weakly expressed in class IV neurons during embryogenesis. Because of the simple and stereotyped dendritic arborization patterns of the dorsally located ddaD and ddaE, the studies of dendrite development focused on these two dorsally located class I neurons (Parrish, 2006).
To establish that RNAi is an efficient method to systematically study dendrite development in the Drosophila embryonic PNS, it was demonstrated that injecting embryos with double-stranded RNA (dsRNA) for green fluorescent protein (gfp) is sufficient to attenuate Gal-4221-driven expression of an mCD8::GFP fusion protein as measured by confocal microscopy. Next whether RNAi could efficiently phenocopy loss-of-function mutants known to affect dendrite development was tested. Similar to the mutant phenotype of short stop (shot), which encodes an actin/microtubule cross-linking protein, shot(RNAi) caused routing defects, dorsal overextension, and a reduction in lateral branching of dorsally extended primary dendrites. Likewise, RNAi of sequoia or flamingo resulted in overextension of ddaD and ddaE, RNAi of hamlet resulted in supernumerary class I neurons, and RNAi of tumbleweed resulted in supernumerary class I neurons and a range of arborization defects, consistent with the reported mutant phenotypes. Thus, RNAi is effective in generating reduction of function phenotypes in embryonic class I dendrites (Parrish, 2006).
In contrast to the genes that coordinately affect dorsal dendrite outgrowth and lateral branching/outgrowth, a group of 21 genes (group B) were identified that have opposing effects on dendrite outgrowth and branching, suggesting that dendrite outgrowth and branching might partially antagonize one another. RNAi of 19 of these genes resulted in dorsal overextension of primary dendrites and a reduction in lateral branching/lateral branch extension. In the most severe cases, such as RNAi of the transcriptional repressor snail, dorsal overextension of almost completely unbranched dendrites was found. Like snail(RNAi), RNAi of the nuclear hormone receptor knirps, the transcriptional repressor l(3)mbt, as well as 15 other genes, all caused dorsal overextension of primary dendrites. As in the case of genes that normally limit arborization, RNAi of these genes rarely caused dendrites to cross the dorsal midline (Parrish, 2006).
Increased dendritic branching also resulted from RNAi of several genes known to affect nervous system development, including Adh transcription factor 1 (Adf1), the zinc finger TF nervy (nvy), the basic helixloophelix (bHLH) TF deadpan (dpn), as well as genes not previously known to affect neuronal function, such as the putative transcription elongation factor Elongin c. Both Adf1 and dpn mutants have defects in larval locomotion and, in light of recent findings suggesting that da neurons may regulate aspects of larval locomotion, it is possible that dendrite defects underlie these behavioral defects. Consistent with its role in class I dendrite development, dpn is expressed in all PNS neurons. Likewise, nervy has been implicated in regulation of axon branching in motorneurons and is apparently expressed in most neurons. Thus, nervy likely regulates multiple aspects of neuronal differentiation. Finally, Elongin C may regulate transcriptional elongation but also likely functions as a component of a multimeric protein complex that includes the von Hippel-Lindau (VHL) tumor suppressor and targets specific proteins for poly-ubiquitination and degradation. Moreover, BTB/POZ domain proteins (such as cg1841 and ab) function as substrate adaptors for cullin E3 ligases. Interestingly, RNAi of a Drosophila homolog (tango) of a known VHL substrate (HIF-1) also affected dendrite arborization. It thus appears that protein degradation pathways regulate dendrite arborization (Parrish, 2006).
As an indication of the hypomorphic nature of many of the alleles and maternal rescue of gene function in mutant embryos, focus was place on dendrite defects that were first apparent during larval stages. For example, a mutant allele of Drosophila Mi-2, which encodes a Hunchback-interacting ATP-dependant chromatin remodeling factor, shows only minor defects in late embryonic stages, but shows an obvious reduction in arborization by 72 h after egg laying. Since Mi-2(RNAi) demonstrates that Mi-2 is required for embryonic dendrite arborization, these findings suggest that Mi-2 is continuously required for class I neurons to maintain proper dendrite arborization patterns. Similarly, the dendritic overbranching associated with a P-element insertion allele of Adf1 was first apparent after embryonic stages, although Adf1(RNAi) caused overbranching in embryos. Class I dendritic arbors of Adf1 mutants are indistinguishable from wild-type neurons until 96 h AEL. By 144 h AEL, ddaE arbors of Adf1 mutants showed a greater than twofold increase in branch number when compared with time-matched wild-type controls. Interestingly, ddaD showed only very minor branching defects in Adf1 mutants, suggesting that ddaD and ddaE might have distinct requirements for Adf1. Similarly, mutant alleles of either E(bx) or Elongin C showed dendrite branching defects only at late larval stages. These findings indicate that Adf1, E(bx), and Elongin C are continuously required to inhibit branching in class I neurons, demonstrating that although class I neurons have very little new branching after embryogenesis, they still retain the capacity to branch (Parrish, 2006).
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date revised: 1 November 2010
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