In two separate hereditary syndromes in the dog, Mullerian duets persist in the presence of testicular tissue: XX sex reversal and the persistent Mullerian Duct Syndrome (PMDS). These are the only known animal models with consistent and specific inherited defects in repression 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 have been proposed, the MIS receptor has not been identified. These models should lead to a more detailed understanding of the genetic control, structure, and mechanisms of action of MIS. In both syndromes, we have shown that failure of Mullerian regression is unlikely to result from an absence of MIS since we have recently shown that testicular tissue of affected 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 insensitivity of the Mullerian system to MIS is due to a defect in timing or amount of MIS. secretion or to a defect in the MIS receptor. These hypotheses will be tested by: 1) Determine whether the synthesis and timing of MIS mRNA and MIS in affected dogs is comparable to that in normal male littermates, and 2) Comparing the location, concentration, and MIS binding characteristics of the MIS receptor in affected dogs and normal littermates. Dogs with XX sex reversal (Cocker Spaniels) and PMDS (Miniature Schnauzers) will be produced by breeding known carriers of these autosomal recessive traits. Production and cellular location of MIS mRNA in testes of normal and affected littermates will be quantitated and compared by Northern blot, in situ hybridization, and immunohistochemical techniques. MIS levels in testes of normal and affected littermates will be determined by Western blot analysis. The MlS receptor will first be identified by antiidiotypic antibodies and subsequently by binding to metabolically-labelled MIS produced by stable cell lines transfected with the recombinant human MIS gene.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
7R01HD019393-05
Application #
3316648
Study Section
Human Embryology and Development Subcommittee 2 (HED)
Project Start
1985-04-01
Project End
1991-11-30
Budget Start
1989-08-01
Budget End
1989-11-30
Support Year
5
Fiscal Year
1989
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; 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; 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; 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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