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
function.
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.
1. Jost, A. Recent Prog. Horm. Res. 8, 379418 (1953).
2. Yu, R.N. et al. Nature Genet. 20, 353357 (1998).
3. Kletter, G.B., Gorski, J.L. & Kelch, R.P. Trends Endocrinol.
Metab. 2, 123128 (1991).
4. Bardoni, B. et al. Nature Genet. 7, 497501 (1994).
5. Zanaria, E. et al. Nature 372, 635641 (1994).
6. Muscatelli, F. et al. Nature 372, 672676 (1994).
7. Swain, A., Zanaria, E., Hacker, A., Lovell-Badge, R. &
Camerino, G. Nature Genet. 12, 404409 (1996).
8. Goodfellow, P.N. & Lovell-Badge, R. Annu. Rev. Genet. 27,
7192 (1993).
9. Swain, A., Narvaez, V., Burgoyne, P., Camerino, G. & Lovell-Badge,
R. Nature 391, 761767 (1998).
10. Parker, K.L. & Schimmer, B.P. Endocrine Rev. 18, 361377
(1997).
11. Ito, M., Yu, R.N. & Jameson, J.L. Mol. Cell. Biol. 17,
14761483 (1997).
12. Crawford, P.A., Dorn, C., Sadovsky, Y. & Milbrandt, J.
Mol. Cell. Biol. 18, 29495629 (1998).
13. Nachtigal, M.W. et al. Cell 93, 445454 (1998).
14. Zazopoulos, E., Lalli, E., Stocco, D.M. & Sassone-Corsi,
P. Nature 390, 311315 (1997).