Sintesi di: Ahch and the feminine mystique
L. Parker & Bernard P. Schimmer, Nature Genetics volume 20 december 1998
The testes and their products impose male sexual differentiation
on an embryo otherwise destined to develop as female with female
sexual differentia-tion acting as a 'default' pathway (1). Analyses
of rare human patients with impaired gonadal development or function-who
develop as phenotypic females irrespective of genetic sex-also
support this model. Over time, the pejorative nature of the term
'default' and the expectation that specific genes program ovarian
development led some investigators to challenge the notion of
a strictly passive pathway of female differentiation. One gene
that has been implicated in ovarian development is AHC (also known
as DAX1). Larry Jameson and colleagues describe the consequences
of targeted disruption of the mouse homologue, Ahch (ref. 2).
Strikingly, loss of Ahch function does not impair ovarian development
or other aspects of female sexual differentiation, but disrupts
spermatogenesis, revealing a previously unsuspected male-specific
Does exist a difference between mice and humans, or does it reflect previous misconceptions of the role of AHC in determining sex?
A candidate female determinant
Deletions or mutation of AHC cause a disorder called adrenal hypoplasia con-genita in humans (3) . Adrenal insufficiency results from impaired development of the steroid-producing zones of the adrenal gland. At puberty, patients exhibit decreased gonadal function due to a compound defect in both hypothalamus and pituitary that impairs gonadotropin production. Duplication of the region of Xp21 that harbours AHC causes 46 XY individuals to develop as females- ( 'dosage sensitive sex reversal' cfr Bardoni et al 1994)- suggesting that Xp21 contains a gene that inhibits male differentiation . (DAX1 alias of AHC, derives from its association with Dosage-sensitive sex reversal, Adrenal hypoplasia congenita, X-chromosome 5,6 ). Its association with dosage-sensitive sex reversal, together with the observation that Ahch expression is upregulated in the mouse ovary coinci-dent with sexual differentiation (7) , led to the proposal that AHC plays a role in the female developmental pathway.
Potential pathways of AHC function
AHC was originally isolated by positional cloning and shown to encode an unusual member of the nuclear hormone receptor family that lacks the typical zinc finger DNA-binding motif but retains the ligand binding domain characteristic of other family members. From its structure one can argue that AHC would regulate the expression of target genes involved in gonadogenesis, perhaps through protein-protein interactions.
Sex reversal in 46 XY patients with AHC duplication suggests that AHC may interfere with SRY function in controlling testes differentiation.. In transgenic mice, overexpression of Ahch causes genotypic XY males to develop as females (9) , directly supporting a role of Ahch in dosage-sensitive sex reversal. In contrast with humans, however, sex reversal is observed only in the setting of a relatively weak Sry allele or an Sry trans-gene, highlighting the modifying influence of genetic background on Ahch function in mice.
The orphan nuclear receptor steroido-genic factor 1 (Sf-1) is another potential target of Ahch regulation. Sf-1 is essential for adrenal and gonadal development, and is believed to regulate genes encoding androgens and Mullerian inhibiting substance (10) , hormones that mediate male sexual differentiation. Ahch can interfere with the transcription of Sf-1 target genes, either by direct protein-protein interactions with Sf-1 (refs 11-13) or by binding to specific DNA sequences in the promoter regions of Sf-1-responsive genes (14) . So far, no women have been identified with mutations or deletions of both AHC alleles. This may be due to a low frequency of mutated AHC alleles or infertility in males with AHC mutations, and has made it impossible to examine the role of AHC in female endocrine development.
Initial efforts for testing the AHC function in XY embryonic stem cells failed-probably because Ahch is required for their growth and differentiation. As an alternate strategy XY and XX mice carrying the mutant Ahch alleles del2 (the second exon it is essential in humans) were generates. In some respects, the adrenal cortex in mice with deleted Ahch resembles that of human patients with adrenal hypoplasia congenita.
The human fetal adrenal cortex originates from mesenchymal tissue in the genital ridge and is comprised of two zones-a prominent fetal zone, which produces adrenal androgens and normally disappears within the first year after birth, and the definitive zone, which gives rise to the adult adrenal cortex. The fetal mouse adrenal contains a group of cells, termed the X zone, whose location within the gland corresponds to that of the human fetal zone. However, the X zone is smaller, does not produce androgens, and regresses at puberty. In both Ahch-deficient mice and human patients, however, cytopathological changes are also observed in the definitive zone, causing postnatal adrenal insufficiency that must be treated by corticosteroid replacement for survival. In contrast, adult adrenal function in the Ahch-deficient mice- which do not require steroid supplementation- is preserved to a considerably greater degree.
Analyses of the reproductive organs of XY mice mutant for Ahch yielded further surprises. Testicular weight is decreased considerably, apparently due to primary testicular defects. The testes appear relatively normal after birth but thereafter exhibit progressive epithelial dysgenesis and sloughing of germ cells, with complete loss of germ cells by 14 weeks. These degenerative changes, which cause male infertility, may be caused by impaired function of Sertoli cells, which normally express Ahch and support spermatogenesis. In contrast, hypogonadism in patients with adrenal hypoplasia congenita presumably results from deficiency of pituitary gonadotropins. Against all expectations, female mice with mutant Ahch exhibit normal sexual maturation, ovulation and fertility; their ovaries have only subtle changes in follicle structure that may reflect impaired granulosa cell function in the absence of Ahch.
Sense and sensibility of sex determination
The disrupted allele would encode a protein with residual biological activity. Although the mutant Ahch allele lacks the second exon, which is essential for function in humans, it still produces transcripts that encode most of the Ahch protein. These aberrant transcripts, however, are present at very low levels, suggesting that truncated Ahch is unlikely to restore significant levels of activity. Alternatively, the differences between human patients and knockout mice may reflect species-specific influences of additional genes on endocrine development. In this case, the Ahch -deficient mouse may provide a powerful tool to identify such genes and to better understand the processes that control adrenal and gonadal development and function. The studies presented here demonstrate that mouse Ahch encodes both an anti-testis factor-acting at criti-cal stages of embryonic sex determina-tion- and an essential factor in spermatogenesis. Future studies will elu- cidate whether AHC plays similar, as yet unappreciated, roles in human endocrine function. Perhaps most importantly, the results of Jameson et al. point out the need for a renewed effort in the search for genes that mediate ovarian determination and differentiation.
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