International Mammalian Genome Society

logo18th International Mouse Genome Conference

17-22 October 2004, Seattle, USA


ORAL PRESENTATION

WEDNESDAY OCTOBER 20

11.30am – 11.45am

THE ADRENOCORTICAL DYSPLASIA (ACD) MOUSE: MUTATION IN A NOVEL GENE CAUSES A PLEIOTROPIC PHENOTYPE OF UROGENITAL DEFECTS AND CAUDAL DYSGENESIS

Hutz JE1, Keegan CE1, Else T1, Adamska M1, Shah SP1, Kent AE1, Looyenga BD1, Howes JM1, Beamer WG2, Hammer GD1

1 University of Michigan, Ann Arbor, MI, United States, 2 The Jackson Laboratory, Bar Harbor, ME, United States

The adrenocortical dysplasia (acd) mouse is a spontaneous autosomal recessive mutant with developmental defects in organs derived from the urogenital ridge: the kidneys, gonads, and adrenals.  Adrenocortical dysplasia and hypofunction are predominant features in surviving adult mice.  Adult female mutant mice exhibit an overall decrease in ovarian folliculogenesis and males have no mature sperm, leading to infertility.  Fifty percent of adult mutants develop hydronephrosis due to ureteral hyperplasia.  Here we report a splice donor site mutation in a novel gene (Ucd1 – Urogenital and Caudal Dysgenesis-1) in acd mice.  Characterization of Ucd1 transcripts produced in acd mutant tissues shows two abnormal transcripts and lack of detectable normal transcript, consistent with a splicing defect.  Expression of a beta-actin-driven Ucd1 cDNA transgene in acd mutants rescues the observed phenotype.  On the original genetic strain (DW/J), mutants are not born in Mendelian ratios.  Analysis of e14.5 mutant embryos reveals a striking caudal regression phenotype and limb defects.  Whole mount in situ hybridization studies at e11.5 reveal normal expression of Shh and a unique Fgf8 expression domain that is expanded in the dorsal-ventral axis but shortened in the anterior-posterior axis of the apical ectodermal ridge.  Expression of Wnt3a and Dll1 in the tail bud is reduced in some mutants and correlates with the observed variability in phenotypic expression.  The combination of caudal regression, limb malformations, and urogenital defects suggests involvement of UCD1 in early embryo patterning regulated by Wnt and retinoic acid signaling.

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