Gene dosage-dependent effects of the <i>Hoxa-13</i> and <i>Hoxd-13</i> mutations on morphogenesis of the terminal parts of the digestive and urogenital tracts

TLDR

Hoxa‑13 and Hoxd‑13 are known to pattern distal limb skeletons and are also expressed in the terminal digestive and urogenital tracts during embryogenesis and postnatal development. The study reports the abnormalities that arise in the digestive and urogenital systems of Hoxa‑13−/− and Hoxa‑13/Hoxd‑13 compound mutant mice. Because Hoxa‑13−/− embryos are lethal, only Hoxa‑13+/−/Hoxd‑13−/− compound mutants survive to adulthood. Hoxa‑13 null embryos lack caudal Müllerian ducts, the urinary bladder, and show premature umbilical artery stenosis, causing mid‑gestation lethality, while Hoxa‑13+/−/Hoxd‑13−/− adults exhibit agenesis or hypoplasia of male accessory glands, mispositioned genital and anal openings, hydronephrosis, rectal layer defects, and double‑null fetuses fail to separate the hindgut into urogenital sinus and rectum, underscoring the essential, partially redundant roles of Hoxa‑13 and Hoxd‑13 in terminal gut and urogenital tract morphogenesis.

Abstract

ABSTRACT 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 embryogenesis and postnatal development. Here, we report the abnormalities occuring in these systems in Hoxa-13−/− and Hoxa-13/Hoxd-13 compound mutant mice. Hoxa-13−/− mutant fetuses show agenesis of the caudal portion of the Müllerian ducts, lack of development of the presumptive urinary bladder and premature stenosis of the umbilical arteries, which could account for the lethality of this mutation at mid-gestational stages. Due to such lethality, only Hoxa-13+/−/Hoxd-13−/− compound mutants can reach adulthood. These compound mutants display: (i) agenesis or hypoplasia of some of the male accessory sex glands, (ii) malpositioning of the vaginal, urethral and anal openings, and improper separation of the vagina from the urogenital sinus, (iii) hydronephrosis and (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 urogenital 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 manner, during early morphogenesis of posterior trunk structures.