In two separate hereditary syndromes in the dog, Mullerian ducts persist in the presence of testicular tissue: Persistent Mullerian Duct Syndrome (PMDS) and XX sex reversal (XXSR). These are the only known animal models with consistent and specific inherited defects in regression of the Mullerian duct system described to date. Preservation of these models for further study depends entirely upon this proposal, since there is no other funding to maintain these animals. Their significance is not only that they are models of human developmental disorders. They are an important resource for understanding the role of Mullerian Inhibiting Substance (MIS) in mammalian reproductive development and function. Although the gene for MIS has been cloned and biochemical mechanisms of its action proposed, the MIS receptor (MIS-R) has only been indirectly identified. These models should lead to a more detailed understanding of the genetic control, structure, and mechanism of action of MIS. In both syndromes, we have shown that failure of Mullerian duct regression is unlikely to result from MIS absence, since testicular tissue of affected neonatal dogs causes regression of embryonic rat Mullerian ducts in an organ culture bioassay. Our objective in the present study is to determine whether the apparent resistance of the Mullerian duct system to MIS is due to a defect in timing or amount of MIS secretion or to a defect in the MIS-R. These hypotheses will be tested by: 1) Determining whether the synthesis and timing of MIS and MIS mRNA in affected embryos is comparable to that of normal male littermates, 2) Identifying the MIS- R in normal and affected embryos during the period of Mullerian duct regression, and 3) Comparing the density, location, concentration, and MIS binding characteristics of the MIS-R in affected and normal littermates. Dogs with PMDS and XXSR will be produced by breeding known carriers of these autosomal recessive traits. Production, cellular location, and biological activity of MIS will be compared in testes of normal and affected embryos by immunohistochemical methods and bioassay. Production and cellular location of MIS mRNA in testes of normal and affected littermates will be compared by Northern blot analysis and in situ hybridization. The MIS-R will first be identified in normal embryos by confocal imaging microscopy. Characteristics of the MIS-R in affected and normal embryos will be compared by competitive binding studies with radiolabeled recombinant human MIS and radiolabeled antiidiotypic antibodies.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
2R01HD019393-08
Application #
3316642
Study Section
Human Embryology and Development Subcommittee 1 (HED)
Project Start
1985-04-01
Project End
1995-02-28
Budget Start
1992-03-01
Budget End
1993-02-28
Support Year
8
Fiscal Year
1992
Total Cost
Indirect Cost
Name
Cornell University
Department
Type
Schools of Veterinary Medicine
DUNS #
City
Ithaca
State
NY
Country
United States
Zip Code
14850
Meyers-Wallen, V N (2012) Gonadal and sex differentiation abnormalities of dogs and cats. Sex Dev 6:46-60
Meyers-Wallen, V N (2009) Review and update: genomic and molecular advances in sex determination and differentiation in small animals. Reprod Domest Anim 44 Suppl 2:40-6
Wu, Xiufeng; Wan, Shengqin; Pujar, Shashikant et al. (2009) A single base pair mutation encoding a premature stop codon in the MIS type II receptor is responsible for canine persistent Müllerian duct syndrome. J Androl 30:46-56
Pujar, S; Meyers-Wallen, V N (2009) A molecular diagnostic test for persistent Mullerian duct syndrome in miniature schnauzer dogs. Sex Dev 3:326-8
Meyers-Wallen, V N; Hurtgen, J; Schlafer, D et al. (1997) Sry-negative XX true hermaphroditism in a Pasa Fino horse. Equine Vet J 29:404-8
Meyers-Wallen, V N; Bowman, L; Acland, G M et al. (1995) Sry-negative XX sex reversal in the German shorthaired pointer dog. J Hered 86:369-74
Meyers-Wallen, V N; Palmer, V L; Acland, G M et al. (1995) Sry-negative XX sex reversal in the American cocker spaniel dog. Mol Reprod Dev 41:300-5
Meyers-Wallen, V N; Lee, M M; Manganaro, T F et al. (1993) Mullerian inhibiting substance is present in embryonic testes of dogs with persistent mullerian duct syndrome. Biol Reprod 48:1410-8
Sommer, M M; Meyers-Wallen, V N (1991) XX true hermaphroditism in a dog. J Am Vet Med Assoc 198:435-8
Meyers-Wallen, V N; Manganaro, T F; Kuroda, T et al. (1991) The critical period for mullerian duct regression in the dog embryo. Biol Reprod 45:626-33

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