Sex determination in mammals is governed by a series of genetic switches that influence cell fate and differentiation during critical periods of development. Remarkably, the primordial fetal gonad is bipotential and the precursor gonadal cells can develop along either a male (testis) or female (ovary) pathway, depending on which genes are expressed. The main goal of this project is to identify key genes that regulate gonadal development and phenotypic sex. To this end, the investigators propose to screen mice for sex-reversal, manifest as XY phenotypic females or as XX phenotypic males, taking advantage of the existing Northwestern University Genome Wide ENU Mutagenesis Center.
The specific aims of this project are:
Aim 1 : To screen progeny of ENU-mutagenized mice for sex reversal. Mice will be characterized genetically for the presence or absence of the Y-chromosomal Sry gone. At age 21 days, they will be classified as phenotypically male or female. This screen will include at least 10,000 mice per year.
Aim 2 : To characterize the gonadal phenotype of mice with sex-reversal. Morphologic, hormonal, histologic, and developmental analyses will be used to characterize the gonadal (testis and ovary) defects associated with sexreversal. Functional analyses will assess spermatogenesis in males or ovulation in females. These initial studies will be followed by more detailed characterizations of altered gene and protein expression using in situ hybridization, quantitative RT-PCR, immunohistology, and western blot studies. Microarray analyses will be used to identify altered genetic pathways, particularly during key stages of gonadal development.
Aim 3 : To perpetuate germline transmission of mutations associated with sex-reversal and gonadal dysgenesis and to map the genetic locus of the defect.
Aim 4 : To act as a national resource for mouse mutants by providing access to phenotypic screening analyses """"""""online"""""""". In addition to listing identified phenotypes online, putative mutants that are heritable will be cryopreserved and made available to the scientific community directly from the Center and through arrangements with an established national distribution center. Gonadal development provides an excellent opportunity to identify genes involved in differential organogenesis. In addition to providing new information about basic mechanisms that regulate gonad development, these studies are also likely to enhance our understanding of gonadal dysgenesis and infertility in humans.
|Weiss, Jeffrey; Hurley, Lisa A; Harris, Rebecca M et al. (2012) ENU mutagenesis in mice identifies candidate genes for hypogonadism. Mamm Genome 23:346-55|
|Harris, Rebecca M; Weiss, Jeffrey; Jameson, J Larry (2011) Male hypogonadism and germ cell loss caused by a mutation in Polo-like kinase 4. Endocrinology 152:3975-85|
|Laronda, Monica M; Jameson, J Larry (2011) Sox3 functions in a cell-autonomous manner to regulate spermatogonial differentiation in mice. Endocrinology 152:1606-15|
|Harris, Rebecca M; Finlayson, Courtney; Weiss, Jeffrey et al. (2010) A missense mutation in LRR8 of RXFP2 is associated with cryptorchidism. Mamm Genome 21:442-9|
|Raverot, Gerald; Weiss, Jeffrey; Park, Susan Y et al. (2005) Sox3 expression in undifferentiated spermatogonia is required for the progression of spermatogenesis. Dev Biol 283:215-25|
|Park, Susan Y; Jameson, J Larry (2005) Minireview: transcriptional regulation of gonadal development and differentiation. Endocrinology 146:1035-42|
|Park, Susan Y; Meeks, Joshua J; Raverot, Gerald et al. (2005) Nuclear receptors Sf1 and Dax1 function cooperatively to mediate somatic cell differentiation during testis development. Development 132:2415-23|
|Jameson, J Larry (2004) Of mice and men: The tale of steroidogenic factor-1. J Clin Endocrinol Metab 89:5927-9|
|Weiss, Jeffrey; Meeks, Joshua J; Hurley, Lisa et al. (2003) Sox3 is required for gonadal function, but not sex determination, in males and females. Mol Cell Biol 23:8084-91|
|Meeks, Joshua J; Crawford, Susan E; Russell, Theron A et al. (2003) Dax1 regulates testis cord organization during gonadal differentiation. Development 130:1029-36|