Sry Expression Level and Protein Isoform Differences Play a Role in Abnormal Testis Development in C57BL/6J Mice Carrying Certain Sry Alleles

Corresponding author: Eva M. Eicher, 600 Main St., Bar Harbor, ME 04609., eme{at}jax.org (E-mail)

Communicating editor: N. A. JENKINS

Transfer of certain Mus domesticus-derived Y chromosomes (Sry^DOM alleles, e.g., Sry^POS and Sry^AKR) onto the C57BL/6J (B6) mouse strain causes abnormal gonad development due to an aberrant interaction between the Sry^DOM allele and the B6-derived autosomal (tda) genes. For example, B6 XY^POS fetuses develop ovaries and ovotestes and B6 XY^AKR fetuses have delayed testis cord development. To test whether abnormal testis development is caused by insufficient Sry^DOM expression, two approaches were used. First, gonad development and relative Sry expression levels were examined in fetal gonads from two strains of B6 mice that contained a single M. domesticus-derived and a single M. musculus-derived Sry allele (B6-Y^POS,RIII and B6-Y^AKR,RIII). In both cases, presence of the M. musculus Sry^RIII allele corrected abnormal testis development. On the B6 background, Sry^POS was expressed at about half the level of Sry^RIII whereas Sry^AKR and Sry^RIII were equally expressed. On an F₁ hybrid background, both Sry^POS and Sry^RIII expression increased, but Sry^POS expression increased to a greater extent. Second, sexual development and Sry expression levels were determined in XX mice carrying a transgene expressing Sry^POS controlled by POS-derived or MUS-derived regulatory regions. In both cases one B6 transgenic line was recovered in which XX transgenic mice developed only testicular tissue but cord development was delayed despite normal Sry transcriptional initiation and overexpression. For three transgenes where B6 XX transgenic mice developed as females, hermaphrodites, or males, the percentage of XX transgenic males increased on an F₁ background. For the one transgene examined, Sry expression increased on an F₁ background. These results support a model in which delayed testis development is caused by the presence of particular DOM SRY protein isoforms and this, combined with insufficient Sry expression, causes sex reversal. These results also indicate that at least one tda gene regulates Sry expression, possibly by directly binding to Sry regulatory regions.

This article has been cited by other articles:

				G. Nikolova, J. S. Sinsheimer, E. M. Eicher, and E. Vilain The Chromosome 11 Region From Strain 129 Provides Protection From Sex Reversal in XYPOS Mice Genetics, May 1, 2008; 179(1): 419 - 427. [Abstract] [Full Text] [PDF]

				Y. Kim, N. Bingham, R. Sekido, K. L. Parker, R. Lovell-Badge, and B. Capel Fibroblast growth factor receptor 2 regulates proliferation and Sertoli differentiation during male sex determination PNAS, October 16, 2007; 104(42): 16558 - 16563. [Abstract] [Full Text] [PDF]

				O. U. Bolden-Tiller, H. Chiarini-Garcia, C. Poirier, D. Alves-Freitas, C. C. Weng, G. Shetty, and M. L. Meistrich Genetic Factors Contributing to Defective Spermatogonial Differentiation in Juvenile Spermatogonial Depletion (Utp14bjsd) Mice Biol Reprod, August 1, 2007; 77(2): 237 - 246. [Abstract] [Full Text] [PDF]

				P. Val, J.-P. Martinez-Barbera, and A. Swain Adrenal development is initiated by Cited2 and Wt1 through modulation of Sf-1 dosage Development, June 15, 2007; 134(12): 2349 - 2358. [Abstract] [Full Text] [PDF]

				G. J. Bouma, K. H. Albrecht, L. L. Washburn, A. K. Recknagel, G. A. Churchill, and E. M. Eicher Gonadal sex reversal in mutant Dax1 XY mice: a failure to upregulate Sox9 in pre-Sertoli cells Development, July 1, 2005; 132(13): 3045 - 3054. [Abstract] [Full Text] [PDF]

				A. Isotani, T. Nakanishi, S. Kobayashi, J. Lee, S. Chuma, N. Nakatsuji, F. Ishino, and M. Okabe Genomic imprinting of XX spermatogonia and XX oocytes recovered from XX{leftrightarrow}XY chimeric testes PNAS, March 15, 2005; 102(11): 4039 - 4044. [Abstract] [Full Text] [PDF]

				S. Y. Park and J. L. Jameson Minireview: Transcriptional Regulation of Gonadal Development and Differentiation Endocrinology, March 1, 2005; 146(3): 1035 - 1042. [Abstract] [Full Text] [PDF]