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).


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).

The bristle patterning genes hairy and extramacrochaetae regulate the development of structures required for flight in Diptera

The distribution of sensory bristles on the thorax of Diptera (true flies) provides a useful model for the study of the evolution of spatial patterns. Large bristles called macrochaetes are arranged into species-specific stereotypical patterns determined via spatially discrete expression of the proneural genes achaete-scute (ac-sc). In Drosophila ac-sc expression is regulated by transcriptional activation at sites where bristle precursors develop and by repression outside of these sites. Three genes, extramacrochaetae (emc), hairy (h) and stripe (sr), involved in repression have been documented. This study demonstrates that in Drosophila, the repressor genes emc and h, like sr, play an essential role in the development of structures forming part of the flight apparatus. It was found that, in Calliphora vicina a species diverged from D. melanogaster by about 100Myr, spatial expression of emc, h and sr is conserved at the location of development of those structures. Based on these findings it is argued, first, that the role emc, h and sr in development of the flight apparatus preceded their activities for macrochaete patterning; second, that species-specific variation in activation and repression of ac-sc expression is evolving in parallel to establish a unique distribution of macrochaetes in each species (Costa, 2013).

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, h7H, display the extreme 'lawn' phenotype, whereas larvae trans-heterozygous for the h7H allele and a weaker h allele, h12C, display the classic pair-rule phenotype. This h7H/h12C 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 h7H allele. Reducing the dose of CtBP maternally results in the suppression of the h7H/h12C mutant cuticle phenotype. Likewise, reducing the dose of CtBP maternally in the severe h7H background suppresses the extreme lawn phenotype. No alterations in viability or phenotype of any progeny classes are observed when P1590 is trans-heterozygous with h7H, or when the h7H 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, nkd7H16 and nkd7E89, and one moderately severe allele, nkd9G33, 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/hnull is lethal, whereas h1/h null is viable (A. Martinez-Arias, personal communication to Zeng, 2000). Therefore clones were generated of the strong allele nkd7E89 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, nkd7H16, but not h +, nkd7E89 or h1, nkd9G33 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 emcpel 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).

The bHLH transcription factor, hairy, refines the terminal cell fate in the Drosophila embryonic trachea

The pair-rule gene, hairy, encodes a basic helix-loop-helix transcription factor and is required for patterning of the early Drosophila embryo and for morphogenesis of the embryonic salivary gland. Although hairy was shown to be expressed in the tracheal primordia and in surrounding mesoderm, whether hairy plays a role in tracheal development is not known. This study reports that hairy is required for refining the terminal cell fate in the embryonic trachea and that hairy's tracheal function is distinct from its earlier role in embryonic patterning. In hairy mutant embryos where the repressive activity of hairy is lost due to lack of its co-repressor binding site, extra terminal cells are specified in the dorsal branches. hairy was shown to function in the muscle to refine the terminal cell fate to a single cell at the tip of the dorsal branch by limiting the expression domain of branchless (bnl), encoding the FGF ligand, in surrounding muscle cells. Abnormal activation of the Bnl signaling pathway in hairy mutant tracheal cells is exemplified by increased number of dorsal branch cells expressing Bnl receptor, Breathless (Btl) and Pointed, a downstream target of the Bnl/Btl signaling pathway. hairy genetically interacts with bnl in TC fate restriction, and overexpression of bnl in a subset of the muscle surrounding tracheal cells phenocopies the hairy mutant phenotype. These studies demonstrate a novel role for Hairy in restriction of the terminal cell fate by limiting the domain of bnl expression in surrounding muscle cells such that only a single dorsal branch cell becomes specified as a terminal cell. These studies provide the first evidence for Hairy in regulation of the FGF signaling pathway during branching morphogenesis (Zhan, 2010).

To date hairy function in epithelial morphogenesis is limited to a previous study on hairy's role in the regulation of apical membrane growth during embryonic salivary gland development. The current study demonstrate a novel function for hairy in refinement of the terminal cell fate to a single cell at the tip of the dorsal branch through restriction of bnl expression domains in muscle cells surrounding tracheal cells. Due to the strong requirement for hairy in early embryonic patterning, it was necessary to distinguish hairy function in tracheal development from its earlier patterning role. Thus, this analysis of hairy function in the trachea was focused on mutations that did not perturb segmentation of the embryo. h47 mutant embryos had no patterning defect, and yet, extra TCs were specified. hACT, which not only lacks the WRPW motif but also contains the transcriptional activation domain of VP16 induces ectopic expression of target genes when expressed in the late blastoderm stage, the time when endogenous Hairy is expressed and is active. Expression of hACT in mid-embryogenesis, prior to specification of the terminal cell fate led to ectopic expression of bnl in muscle cells and specification of extra TCs. Since hACT was induced after patterning of the early embryo was complete, there were no segmentation defects in hACT-expressing embryos and yet, extra TCs were specified. Similar to hACT, in h674 mutant embryos with no segmentation defect, bnl expression domain was expanded and extra TCs were specified. Since, h674, like hACT, lacks the C-terminal co-repressor binding WRPW tetrapeptide it is possible that the Hairy mutant protein of h674 embryos also acts as an activator and induces expression of downstream target genes. Thus, the h47, h674and hACT mutant embryos which are segmented properly and yet show specification of extra TCs in the tracheal dorsal branches provide evidence that hairy's role in early patterning and in tracheal development are indeed distinct (Zhan, 2010).

In addition to a role for hairy in refinement of the terminal cell fate through regulation of bnl expression in muscle cells, evidence is provided that hairy and bnl act antagonistically to regulate terminal branch lumen length. These studies provide the first evidence for a role for bnl in tracheal lumen size control. Although hairy mutant tracheal cells invaginated completely, they did so in an uncoordinated manner compared to wild-type. Thus, hairy function is required at multiple stages of tracheal development (Zhan, 2010).

The data support a model where Hairy in the somatic muscle, normally refines the spatial expression of bnl in the muscle cells that are in close proximity to the migrating tracheal branches, such that only a single cell at the tip of each dorsal branch becomes specified as the terminal cell. Upon loss of Hairy's repressive activity, bnl expression expands in the muscle cells and abnormally activates the bnl/btl signaling pathway, such that extra TCs become specified. These data do not suggest whether bnl is a direct or indirect transcriptional target of Hairy; future studies will distinguish between these two possibilities. It is also possible that Hairy regulates bnl/btl signaling and TC specification via mechanisms other than control of bnl expression. For example, it was recently shown that in the developing tracheal air sac of Drosophila larvae, matrix metalloprotease Mmp2 spatially restricts FGF signaling. Thus, hairy may modulate the extent of bnl/btl signaling in tracheal cells in a post-translational manner as well (Zhan, 2010).

The role of the bHLH protein hairy in morphogenetic furrow progression in the developing Drosophila eye

In Drosophila eye development, a wave of differentiation follows a morphogenetic furrow progressing across the eye imaginal disc. This is subject to negative regulation attributed to the HLH repressor proteins Hairy and Extramacrochaete. Recent studies identify negative feedback on the bHLH gene daughterless as one of the main functions of extramacrochaete. This study assessed the role of hairy in relation to daughterless and other HLH genes. Hairy was not found to regulate the expression of Daughterless, Extramacrochaete or Atonal, and Hairy expression was largely unregulated by these other genes. Null alleles of hairy did not alter the rate or pattern of differentiation, either alone or in the absence of Extramacrochaete. These findings question whether hairy is an important regulator of the progression of retinal differentiation in Drosophila, alone or redundantly with extramacrochaete (Bhattacharya, 2012).

The morphogenetic furrow moves anteriorly across the eye disc under the positive influence of Hh and Dpp. The forward progression of differentiation is a consequence of the positive activation of Ato expression as well as the parallel repression of Emc, which results in elevated levels of the heterodimer partner of Ato, Da. Hh and Dpp also affect the cell cycle, the shapes of cells in the morphogenetic furrow, the expression of retinal determination genes, and the sizes of nucleoli, although it remains to be determined whether these other processes contribute directly to neural differentiation (Bhattacharya, 2012).

This paper addresses hairy, a potential barrier to morphogenetic furrow movement. Hairy protein is expressed through much of the eye disc anterior to the morphogenetic furrow, and is downregulated sharply at the time that Atonal becomes active. Although clones of hairy null mutations do not affect eye differentiation, it has been thought that hairy acts along with emc. so that emc hypomorphs that have no effect on the morphogenetic furrow progression alone do speed up the furrow in combination with hairy null mutations. It has been proposed that Hairy is a marker of a 'preproneural state', in which the presence of Hairy helps restrain incipient neurogenesis (Bhattacharya, 2012).

If hairy acts redundantly with emc, this might be explained by convergence on common targets, since both encode transcriptional repressors. This study found, however, no noticeable effect of hairy null alleles on Da expression, Emc expression, or Ato expression. In addition, h emc double mutant clones appeared to have no additional effect on Da expression from that seen in emc clones. Since no obvious role for hairy in the expression of these genes was detected, the progression of the morphogenetic furrow was measured directly. Although differentiation progresses faster through cells null for emc than through wild type cells, removing hairy had no further effect on morphogenetic furrow progression. These findings provide no evidence that hairy acted redundantly with emc, since it did not regulate morphogenetic furrow progression or target gene expression when emc function was removed, implying that hairy function was not sufficient to compensate even partially for the absence of emc. In fact, a hairy null mutation has no discernible effect on the morphogenetic furrow in either the presence or absence of emc. There may be a small role for emc in regulating Hairy expression, such that Hairy is repressed slightly faster in the absence of emc, but even the complete absence of hairy has no effect on furrow progression, either in the presence or absence of emc. In conjunction with experiments in which Hairy did not affect morphogenetic furrow progression when over-expressed, these findings challenge the model that Hairy regulates morphogenetic furrow progression (Bhattacharya, 2012).

The role for hairy in regulating morphogenetic furrow progression was suggested because hairy antagonizes neurogenesis in other imaginal discs, and because hairy mutations enhanced the phenotype of the emc1 mutant allele. In addition, failure to downregulate Hairy at the morphogenetic furrow correlates with reduced differentiation in a number of mutant genotypes. The neurogenic phenotype of hairy in other imaginal discs depends on Hairy binding to the enhancer of achaetae. Since achaetae is not expressed or functional during morphogenetic furrow progression, these data offer no basis for predicting hairy function in the eye (Bhattacharya, 2012).

Enhancement of the emc1 allele, but not the emcAP6 null allele, could be explained if hairy contributed to emc function in some way, so that hairy function can mitigate partial loss of emc function by increasing the effectiveness of the remaining Emc protein, but would not affect the emc null phenotype. The emc1mutant allele encodes a Val-to-Glu substitution in the HLH domain, which would be expected to interfere with heterodimer formation by Emc1 protein, consistent with a hypomorphic phenotype. No evidence was found that hairy contributed to the expression of Emc or to Emc function as a negative regulator of da. Another possibility is that Hairy protein might act through distinct mechanisms in addition to binding to specific DNA sequences. The E(spl) proteins, which contain similar domains to Hairy, can also repress gene expression when targeted to particular genes by protein-protein interactions. It has not been tested whether Hairy might exhibit similar protein-protein interactions. It is also reported that the Chicken Id protein, a homolog of Emc, interacts directly with Hes1, a homolog of Hairy. Thus far, however, Drosophila Hairy is not known to heterodimerize with Emc or any of its proneural gene targets. It is possible that Hairy might regulate da transcription in a subtle way only revealed in the emc1 backgrounds. For example, Hairy repression of da transcription might be redundant in the presence of wild type emc, and not sufficient to impact da autoregulation in the complete absence of Emc. Detailed information concerning the thresholds of da transcription under different conditions would be required to assess this model (Bhattacharya, 2012).

The Hairy expression ahead of the morphogenetic furrow certainly seems to provide a marker of an early stage of eye development. Consistent with this, retention of Hairy expression in mutant genotypes correlates with diminished retinal differentiation. The findings of this study indicate that, contrary to previous models, any contribution of Hairy to morphogenetic furrow progression is quite limited, and there is little evidence to connect it with emc. The possibility remains that hairy may function in a subtle way, perhaps redundantly with other genes, or affect processes other than furrow progression, particularly since many questions remain to be resolved concerning the transcriptional regulation of eye development, such as how ato expression is initiated as the furrow progresses, or all the mechanisms by which the retinal determination genes contribute to eye development. It is also possible that laboratory conditions conceal the contribution of the hairy gene in eye development, as has been suggested for regulatory pathways that are thought to contribute temperature stability in variable environments (Bhattacharya, 2012).


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hairy: Biological Overview | Evolutionary Homologs | Regulation | Protein Interactions and Post-transcriptional Regulation | Developmental Biology | Effects of Mutation

date revised: 20 August 2014

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