Gene name - hermaphrodite
Cytological map position - 36A1--36A9
Function - transcription factor
Keywords - sex determination
Symbol - her
FlyBase ID: FBgn0001185
Genetic map position - 2-52.9
Classification - C2H2 zinc finger
Cellular location - nuclear
Studies of hermaphrodite reinforce the view that there are two classes of genes in the somatic sex determination hierarchy. The first class includes genes with sex-specific expression, such as Sex lethal, transformer, fruitless and doublesex, and also genes that are expressed at higher levels in one sex than the other, such as the X-linked zygotic activators of Sxl [ sisterless-a (sis-a), sis-b (also known as scute), sisterless-c (sis-c) and runt]. Members of this class of genes play instructional roles in sex determination and differentiation.
Members of the second class of genes are not sex specific in terms of their expression, such as the genes that act to facilitate Sxl auto-regulation [sans fille (snf), fl(2)d and virulizer]; the maternal or autosome-linked zygotic regulators of Sxl [daughterless (da), extra machrochaetae (emc), groucho (gro) and deadpan (dpn)], and the gene tra-2. These genes play permissive roles in sex determination and differentiation. Because hermaphrodite's expression is not sex specific, her falls into this second class. Most of the genes in the first class and all of the genes in the second class have functions other than sex determination and differentiation. Thus, of all the genes known to be required for sex determination, only three (Sxl, tra and doublesex) act exclusively in sex determination and/or differentiation, supporting the view that genes participating exclusively in one specific developmental process are rare (Li, 1998a and references).
Where in the sex determination pathway does her fit? Sex lethal is a good place to start looking for an answer: with respect to its role in female somatic sexual differentiation, Sxl is the master regulator of sex determination in Drosophila protein; it directs the splicing of the transformer (tra) pre-mRNA to generate a functional mRNA in females. In males, tra pre-mRNA is spliced in a default pattern that leaves premature stop codons in the mRNA. Downstream of tra, the somatic sex determination pathway splits into two branches: one contains the doublesex (dsx) gene and the other the fruitless (fru) gene. In females, Tra acts together with Transformer-2 (Tra-2) to direct the splicing of the DSX pre-mRNA to generate a female-specific mRNA. Neither gene is expressed sex-specifically in the soma. In males, where functional Tra is present, default splicing of DSX pre-mRNA produces the male-specific DSX mRNA. DSX proteins are sex-specific transcription factors that are required for all aspects of somatic sexual differentiation outside of the CNS. The female-specific DSX protein (DSX F) acts together with the products of the hermaphrodite (her) and the intersex (ix) genes to repress male differentiation and to promote female differentiation in females; conversely, the male-specific DSX protein (DSX M) acts to repress female differentiation and to promote male differentiation in males (Li, 1998a and references).
Hermaphrodite has both maternal and zygotic functions. Maternally, as well as zygotically, her has certain functions that are involved in sex determination/differentiation and other functions that are essential for both sexes. Although the exact nature of the non-sex-specific vital functions of her is unknown, significant insights have been gained into the nature of her's sex determination/differentiation functions (Pultz, 1994 and Pultz, 1995). The maternal sex determination function of her is required for the activation of the early promoter of Sxl. It is unknown whether the her maternal sex-specific function regulates the Sxl early promoter directly, or indirectly, through other regulators of Sxl. With respect to the zygotic sex differentiation function of her in females, it has been shown that her does not regulate the expression of Sxl, tra or dsx at the level of either transcription or the splicing of their pre-mRNAs. These results have led to the suggestion that the female-specific zygotic function of her acts in parallel with, or downstream of, dsx (Pultz, 1995).
Zygotically, her+ function is required for female sexual differentiation: when zygotic her+ function is lacking, chromosomal females (females carrying two X chromosomes) are transformed to intersex females. The her female sexual differentiation phenotype is a "true intersex" phenotype similar to that of doublesex and intersex. In "true intersex" individuals, each cell is intersexual; in contrast, "mosaic intersex" individuals have a mixture of cells, some with male-like and others with female-like morphologies. One indicator of a "true intersex" phenotype is seen in the female counterparts of the male sex comb bristles found on the first tarsal segment of mesothoracic and metathoracic legs of adult males. Wild-type males have a row of about 9-14 enlarged, blunt bristles; the row is rotated to an orientation approximately perpendicular to the bristle rows on the metatarsus. In contrast, wild-type females have a row of about 3-8 tapered bristles that is approximately parallel to the other bristle rows. In "true intersexes" the row is partially oriented toward the male orientation, as is seen in chromosomal females with impaired her function. The number of bristles in the rotated row is also increased. The pigmentation of the abdomen and the morphology of genitalia and analia are also intersexual in her females. In wild-type females, the fifth abdominal segment is pigmented only along the posterior margin, whereas in wild-type males, this segment is completely pigmented. In strongly transformed females lacking normal her function, pigmentation extends through the anterior of the fifth abdominal segment. Lack of her function also has effects on males that may indicate a weak transformation to intersexuality. Thus, zygotic her+ function may also play a role in male sexual differentiation (Pultz, 1994).
All of the her cDNAs are derived from the same open reading frame (ORF), but differ in the lengths of their 3' untranslated regions (3'UTRs), because of the use of alternative polyadenylation sites. Of the five cDNAs whose 3' ends were sequenced, two have a poly(A) sequence beginning at nucleotide position 2229, two at nucleotide position 2360 and one cDNA ends at nucleotide position 2885 without a poly(A) sequence. Since poly(A) addition usually occurs about 10~50 nt 3' of the AAUAAA signal, the AAUAAA signals at positions 2215, 2348 and 2879 are probably used for poly(A) addition. Comparison of the genomic and cDNA sequences reveals that the her gene has two small introns; the first one is 66 nt long and the second 60 nt long. Although there are four polyadenylation signals in the HER 3'UTR, the frequencies of their usage are different. The polyadenylation signals at nucleotide positions 2731 and 2779 are not used frequently because the sizes of these predicted transcripts would be at least 2.470 kb, while the sizes of the majority of the HER transcripts on the northern blot fall between 1.9 kb and 2.2 kb (Li, 1998).
Bases in 5' UTR - 420
Exons - 3
Bases in 3' UTR - 991 (longest)
The Her protein sequence consists of two domains, the N-terminal domain containing four C2H2-type zinc fingers, and the C-terminal domain, which has no known structural motifs. The zinc fingers in the HER protein suggest that it is likely to function as a transcription factor. However, all four of the her zinc fingers deviate substantially from the consensus sequences of the C2H2-type zinc finger motifs. Most notably, the highly conserved aromatic residue (F or Y) at position 12 is replaced by an S or a T residue; the conserved basic residue (K or R) at position 10 is replaced by an Y residue (Li, 1998).
To estimate frequencies of the HER-type changes at position 10 and 12 among known C2H2-type zinc finger motifs, a search of the PIR database was carried out. There were 2314 C2H2 motifs in 522 polypeptides. 87% of them have an F or Y at position 12 and 78% have a K or R at position 10. Only 3.4% (78 out of 2314) are HER-type motifs, having both a Y at position 10 and an S/T at position 12. Remarkably, all except 8 of the 78 HER-type zinc fingers are encoded by the X and Y chromosome genes Zinc Finger X (ZFX) and Zinc Finger Y (ZFY) and their homologs from frog, alligator, chicken, mouse and human (their protein products are referred to as ZFY-like proteins hereafter). These fingers correspond to the even-numbered fingers of the ZFY-like proteins. Detailed structural studies have shown that the residue substitutions in ZFY even-numbered fingers retain the beta-beta-alpha secondary structural motif common to most C2H2 zinc fingers with known three-dimensional structures. However, they do alter internal architecture and surface topology relevant to the putative DNA contacting surface. Another feature shared by the zinc fingers of HER and ZFY-like proteins is a pairwise repeat pattern: odd-numbered or even-numbered fingers are more similar to each other than are odd-numbered fingers to even-numbered fingers. No significant sequence similarity is found between HER and ZFY-like proteins outside the zinc fingers (Li, 1998 and references).
date revised: 8 April 98
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