A better understanding of mammalian gonad development and sex determination is important for both biomedical and basic scientific reasons. A number of sex determination genes have been identified and characterized; however the position and relationship of these genes within the pathway remain to be defined. Many of these genes are implicated in pathological processes in humans, and have essential roles in the normal development of organs other than the gonads. In humans, heterozygous mutations in WT1 (Wilms' tumor-1) or SF1 (Steroidogenic factor-1) are associated with XY sex reversal. In contrast, on most genetic backgrounds XY mice heterozygous for null alleles of Wt1 or Sf1 (Wt1+/- or Sf1+/-) are normal males. Preliminary analysis, however, indicates that on a C57BL/6J-Y AKR (B6-Y AKR) genetic background both Wt1+/- and Sf1+/- mice are XY sex reversed. These heterozygous mice offer distinct advantages over homozygous null mice in investigating the roles of Sf1 and Wt1 in sex determination and gonadogenesis because their gonadal phenotype is less severe and they are viable. We hypothesize that the B6 alleles of Wt1 and Sf1 are hypomorphs and that this reduced function causes decreased expression of Sry, the Y chromosome testis determining gene. We also hypothesize that Wt1 B6 and Sf1 B6 function as hypomorphs only when other interacting genes are homozygous for B6 alleles. These hypotheses will be tested with two specific aims: 1) Determine if Wt1B6 and Sf1 B6 function as hypomorphs and if so, determine why, and 2) Determine the molecular mechanism of sex reversal in B6 XY AKRWt1+/- and B6 XY AKRSf1+/- mice. To accomplish these aims, morphogenesis and marker gene expression in fetal gonads will be examined to determine at what point testis determination becomes aberrant and which genes are affected. Genetic crosses will be used to ascertain if Wt1B6 and Sf1B6 themselves are hypomorphs or if they act as hypomorphs only in cooperation with one or more B6-derived genes. If the latter is true, these modifier genes will be genetically mapped as a first step to identifying them. Furthermore, comparative DNA sequence analysis, and a targeted mutation approach in mice, will be used to identify the changes that cause Wt1B6 and Sf1B6 to have reduced function.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD042779-03
Application #
6871368
Study Section
Mammalian Genetics Study Section (MGN)
Program Officer
Taymans, Susan
Project Start
2003-07-07
Project End
2008-04-30
Budget Start
2005-05-01
Budget End
2006-04-30
Support Year
3
Fiscal Year
2005
Total Cost
$290,700
Indirect Cost
Name
Boston University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
604483045
City
Boston
State
MA
Country
United States
Zip Code
02118
Correa, Stephanie M; Washburn, Linda L; Kahlon, Ravi S et al. (2012) Sex reversal in C57BL/6J XY mice caused by increased expression of ovarian genes and insufficient activation of the testis determining pathway. PLoS Genet 8:e1002569
Lee, Hyunjoo J; Pazin, Dorothy E; Kahlon, Ravi S et al. (2009) Novel markers of early ovarian pre-granulosa cells are expressed in an Sry-like pattern. Dev Dyn 238:812-25
Liu, Peijun; Pazin, Dorothy E; Merson, Rebeka R et al. (2009) The developmentally-regulated Smoc2 gene is repressed by Aryl-hydrocarbon receptor (Ahr) signaling. Gene 433:72-80
Pazin, Dorothy E; Albrecht, Kenneth H (2009) Developmental expression of Smoc1 and Smoc2 suggests potential roles in fetal gonad and reproductive tract differentiation. Dev Dyn 238:2877-90
Liu, Libin; Brown, Dennis; McKee, Mary et al. (2008) Deletion of Cavin/PTRF causes global loss of caveolae, dyslipidemia, and glucose intolerance. Cell Metab 8:310-7
Bouma, Gerrit J; Washburn, Linda L; Albrecht, Kenneth H et al. (2007) Correct dosage of Fog2 and Gata4 transcription factors is critical for fetal testis development in mice. Proc Natl Acad Sci U S A 104:14994-9
Bouma, Gerrit J; Albrecht, Kenneth H; Washburn, Linda L et al. (2005) Gonadal sex reversal in mutant Dax1 XY mice: a failure to upregulate Sox9 in pre-Sertoli cells. Development 132:3045-54