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Role of Ahch in gonadal development and gametogenesis

Abstract

Ahch (also known as Dax1) encodes a transcription factor that has been implicated in sex determination and gonadal differentiation1,2,3. Mutations in human AHC cause X-linked, adrenal hypoplasia congenita (AHC) and hypogonadotropic hypogonadism4,5 (HH). Duplication of the Xp21 dosage-sensitive sex reversal (DSS) region, which contains the Ahch locus1, and transgenic overexpression of Ahch (ref. 6) cause male-to-female sex reversal. Using Cre-mediated disruption of Ahch, we have generated a mouse model of AHC-HH that allows the function of Ahch to be examined in both males and females. Although Ahch has been postulated to function as an ovarian determination gene2,6, the loss of Ahch function in females does not affect ovarian development or fertility. Ahch is instead essential for the maintenance of spermatogenesis. Lack of Ahch causes progressive degeneration of the testicular germinal epithelium independent of abnormalities in gonadotropin and testosterone production and results in male sterility. Ahch is thus not an ovarian determining gene, but rather has a critical role in spermatogenesis.

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Figure 1: Targeted mutagenesis of Ahch.
Figure 2: Adrenal gland histology in Ahch-deleted mice.
Figure 3: Effect of Ahch mutation on testicular histology and spermatogenesis.
Figure 4: Formation of abnormal ovarian follicles in Ahch mutant mice.
Figure 5: Model for Ahch control of testicular development.

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Acknowledgements

We thank L. Samuelson and P. Gillespie for invaluable instruction in ES cell techniques and gene targeting; A. Nagy, R. Nagy and W. Abramow-Newerly for providing the R1 ES cells; R. Mulligan for providing the pPNT targeting vector; K. Foley and R. Eisenman for providing the CMV-Cre transgenic mice; B. Mann for performing the serum hormone radioimmunoassays; A. Parlow for the FSH and LH radioimmunoassay reagents; T. Woodruff, E.-J. Lee, Y. Park, J. Achermann, W. Duan, J. Rutishauser and P. Kopp for helpful discussions; J. Shavit and H. Burrows for experimental advice and reagents; and T. Kotlar, L. Sabacan and K. Stanfield for excellent technical assistance. This work was supported by the NICHD National Cooperative Program for Infertility Research (NIH grant U54-HD-29164), PO1-HD-21921, P30-HD-28048 and by NIH training grant (T32-DK-07169) to R.N.Y.

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Correspondence to J. Larry Jameson..

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Yu, R., Ito, M., Saunders, T. et al. Role of Ahch in gonadal development and gametogenesis. Nat Genet 20, 353–357 (1998). https://doi.org/10.1038/3822

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