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Ureteric Bud Apoptosis and Renal Hypoplasia in Transgenic PAX2-Bax Fetal Mice Mimics the Renal-Coloboma Syndrome

Alison Dziarmaga^*, Patsy Clark, Cherie Stayner, Jean Pierre Julien, Elena Torban^¶, Paul Goodyer^*, and Michael Eccles^,

*Department of Human Genetics, McGill University, Montreal, Quebec, Canada; Department of Paediatrics, Montreal Children’s Hospital, McGill University, Montreal, Quebec, Canada; Department of Pathology, University of Otago, Dunedin, New Zealand; Centre for Research in Neuroscience, Montreal General Hospital, McGill University, Montreal, Quebec, Canada; and ^¶Department of Biochemistry, McGill University, Quebec, Canada.

Correspondence to Dr. Michael Eccles, Department of Pathology, University of Otago, Dunedin 9015, New Zealand. Phone: +64-3479-7878; Fax: +64-3479 7139;

ABSTRACT. In humans, PAX2 haploinsufficiency causes renal-coloboma syndrome (RCS) involving eye abnormalities, renal hypoplasia, and renal failure in early life. The authors previously showed that heterozygous mutant Pax2 mice have smaller kidneys with fewer nephrons, associated with elevated apoptosis in the ureteric bud (UB). However, PAX2 may have a variety of developmental functions such as effects on cell fate and differentiation. To determine whether apoptosis alone is sufficient to cause a UB branching deficit, the authors targeted a pro-apoptotic gene (Bax) to the embryonic kidney under the control of human PAX2 regulatory elements. The exogenous PAX2 promoter directed Bax gene expression specifically to the developing kidney UB, eye, and mid/hindbrain. At E15.5 PAX2Promoter-Bax fetal mice exhibited renal hypoplasia, elevated UB apoptosis, and retinal defects, mimicking the phenotype observed in RCS. The kidneys of E15.5 PAX2Promoter-Bax fetal mice were 55% smaller than those of wild-type fetal mice, and they contained 70% of the normal level of UB branching. The data indicate that loss of Pax2 anti-apoptotic activity is sufficient to account for the reduced UB branching observed in RCS and suggest that elevated UB apoptosis may be a key process responsible for renal hypoplasia. The authors propose a morphogenic unit model in which cell survival influences the rate of UB branching and determines final nephron endowment. E-mail: meccles@otago.ac.nz

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