GENE DOSAGE-DEPENDENT EFFECTS OF THE HOXA-13 AND HOXD-13 MUTATIONS ONMORPHOGENESIS OF THE TERMINAL PARTS OF THE DIGESTIVE AND UROGENITAL TRACTS

Gene targeting experiments have shown that the murine Hoxa-13 and Hoxd -13 paralogous genes control skeletal patterning in the distal region of the developing limbs, However, both genes are also expressed in the terminal part of the digestive and urogenital tracts during embryogen esis and postnatal development, Here, we report the abnormalities occu ring in these systems in Hoxa-13(-/-) and Hoxa-13/Hoxd-13 compound mut ant mice, Hoxa-13(-/-) mutant fetuses show agenesis of the caudal port ion of the Mullerian ducts, lack of development of the presumptive uri nary bladder and premature stenosis of the umbilical arteries, which c ould account for the lethality of this mutation at mid-gestational sta ges, Due to such lethality, only Hoxa-13(+/-)/Hoxd-13(-/-) compound mu tants can reach adulthood, These compound mutants display: (i) agenesi s or hypoplasia of some of the male accessory sex glands, (ii) malposi tioning of the vaginal, urethral and anal openings, and improper separ ation of the vagina from the urogenital sinus, (iii) hydronephrosis an d (iv) anomalies of the muscular and epithelial layers of the rectum, Thus, Hoxa-13 and Hoxd-13 play important roles in the morphogenesis of the terminal part of the gut and urogenital tract, While Hoxa-13(-/-) /Hoxd-13(+/-) fetuses show severely impaired development of the urogen ital sinus, double null (Hoxa-13(-/-)/Hoxd-13(-/-)) fetuses display no separation of the terminal (cloacal) hindgut cavity into a urogenital sinus and presumptive rectum, and no development of the genital bud, thereby demonstrating that both genes act, in a partly redundant manne r, during early morphogenesis of posterior trunk structures.