We are studying animal models of inherited human disorders as a means to understand sex determination and differentiation at the molecular level. By studying systems in which abnormal sexual differentiation occurs, we hope to identify specific genes which are necessary to normal differentiation.

Currently, we are investigating the genetic etiology of three disorders of male sexual differentiation. The first, which occurs in humans and dogs, is Persistent Mullerian Duct Syndrome (PMDS) in which the oviducts and uterus develop in otherwise normal males. We have shown that the Mullerian ducts of canine PMDS-affected embryos fail to bind MIS. Our hypothesis is that a mutation in the MIS receptor is responsible for this dysfunction.

The second disorder that we are investigating is XX Sex Reversal, which occurs in humans and dogs. Affected individuals do not have a Y chromosome: the karyotypes of affected individuals are the same as those of normal females. However, affected individuals develop testicular tissue. We have shown that affected dogs do not have a translocation of the Sry gene from the Y chromosome to a different chromosome. This disorder is caused by a unknown gene mutation and is inherited as an autosomal recessive trait. We are presently performing linkage analysis to determine the cause of this disorder.

The third disorder is canine cryptorchidism, which is the failure of one or both testes to descend into the scrotum. Unilaterally cryptorchid dogs have only one testis in the scrotum. Bilaterally cryptorchid dogs have no testes in the scrotum. In the dog, both testes normally descend into the scrotum by 2 weeks after birth (even though one can not really feel them there at the time), but should be detectable in the scrotum by 6 weeks of age. Testis descent in the dog is thought to be controlled by at least 3 genes, which are unknown. Recessive mutations in such genes result in cryptorchidism. The recently published canine genome sequence allows us to study dog genes more effectively. Using this information, we and our collaborators studying human and mouse cryptorchidism have performed pilot studies in dogs. We have not yet found mutations causing cryptorchidism, but we need to examine many more dogs, their related family members, and dogs of several breeds. All participants are purebred dogs, but their identities and those of their owners are held in confidence. That is, the identity of dogs and owners will be not be revealed by the researchers at any time. Our final goal in all these projects is to produce practical tests to easily identify carriers of these traits. We hope that our research will benefit purebred dogs by facilitating the production of reproductively sound lines of all breeds.

Laboratory techniques that we use are polymerase chain reaction (PCR), reverse-transcription PCR (RTPCR), quantitative RTPCR (q-RTPCR), whole mount in situ hybridization with riboprobes, linkage analysis using microsatellite markers, cloning and sequencing, Southern and Northern blotting, and confocal microscopy.

SELECT PUBLICATIONS

1. Brittain D, Concannon PW, Flanders JA, Flahive WJ, Lewis BL, Meyers-Wallen VN, Moise NS. 1995. Use of surgical intrauterine insemination to manage infertility in a colony of research German shepherd dogs. Laboratory Animal Science 45:404-407.
2. Ellington JE, Meyers-Wallen VN, Ball BA. 1995. Establishment of a coculture system for canine sperm and uterine tube epithelial cells. Vet Record 136:542-543.
3. Meyers-Wallen VN, Hurtgen J, Schlafer D, Tulleners E, Cleland WR, Ruth GR, Acland GM. 1997. Sry-negative XX true hermaphroditism in a Pasa Fino Horse. Eq Vet J 29(5):404-408.
4. Meyers-Wallen VN, Schlafer D, Barr I, Lovell-Badge R, Keyzner A. 1999. Sry-negative XX sex reversal in purebred dogs. Molec Reprod Dev 53:266-273.
5. Hubler M, Hauser B, Meyers-Wallen VN and Arnold S. 1999. Sry-negative XX true hermaphrodite in a Basset Hound. Theriogenology 51:1391-1403.
6. Drew WL, Meyers-Wallen VN, Acland GM, Guyer CL and Steinheimer DN. 1999. Presumptive Sry-negative XX sex reversal in a llama with multiple congenital anomalies. J Am Vet Med Assoc 215:1134-1139.
7. Kutzler MA, Mohammed HO, Lamb SV, and Meyers-Wallen VN. 2003. Accuracy of canine parturition date prediction from the initial rise in preovulatory progesterone concentration. Theriogenology 60:1187-1196.
8. Kutzler MA, Yeager AE, Mohammed HO, and Meyers-Wallen VN. 2003. Accuracy of canine parturition date prediction using fetal measurements obtained by ultrasonography to estimate gestational age. Theriogenology 60:1309-1317.
9. Meyers-Wallen, VN. 2003. Sry and Sox9 expression during canine gonadal sex determination assayed by quantitative reverse-transcription polymerase chain reaction. Molec Reprod Dev 65: 373-381.
10. Kothapalli K, Kirkness E, Natale L, and Meyers-Wallen VN. 2003. Exclusion of PISRT1 as a candidate locus for canine Sry-negative XX sex reversal. Anim Genet 34:467-469.
11. Meyers-Wallen, VN. 2003. Ethics and genetic selection in purebred dogs. Reprod Domest Anim 38:73-76.