Induction of Wnt5a-Expressing Mesenchymal Cells Adjacent to the Cloacal Plate Is an Essential Process for Its Proximodistal Elongation and Subsequent Anorectal Development

Abstract

Anorectal malformations encompass a broad spectrum of congenital defects and are related to the development of the genital tubercle, including the cloacal plate and urorectal septum. To explore the cellular and molecular basis of anorectal malformations, we analyzed the pathogenetic process using two mouse models: Danforth's short tail (Sd) and all-trans retinoic acid (ATRA)-treated mice. Embryologically, the cloacal plate may be divided into distal and proximal parts, with the distal part subdivided into ventral and dorsal parts. In the two mouse models, anorectal malformations occur due to improper development of the proximal part of the cloacal plate. At 10.5 days postcoitus (dpc), in Sd homozygotes, there was a lack of Shh expression only in the cloacal plate and the endoderm around the cloacal plate. In addition, Wnt5a was not expressed in the mesoderm adjacent to the cloacal plate in the two mouse models, and Axin2, which is regulated by Wnt signaling, was not expressed in the dorsal part of the cloacal plate at 12.5 dpc. Based on these results, we suggest that Wnt5a, which is downstream of Shh signaling, and Axin2 affect the development of the proximal part of the cloacal plate.

In vivo knockdown of Brachyury results in skeletal defects and urorectal malformations resembling caudal regression syndrome

“…Several mouse models have been examined which exhibit caudal and/or notochord defects, and these are often accompanied by secondary urorectal anomalies (for examples see GluecksohnSchoenheimer, 1943;Nakata et al, 2009;Padmanabhan, 1998;Seifert et al, 2009;van de Ven et al, 2011). Moreover, the axial defects we observed strongly resembled those present in caudal regression syndrome, where posterior skeletal abnormalities are associated with urorectal malformations (Boulas, 2009;Duhamel, 1961;Renshaw, 1978).…”

Concerted involvement of Cdx/Hox genes and Wnt signaling in morphogenesis of the caudal neural tube and cloacal derivatives from the posterior growth zone

“…Other genetic factors have been considered in the etiology of the Caudal Regression Syndrome, such as Shh and its proposed downstream signaling effectors Wnt5a and Bmp4 (Mandhan et al, 2006;Nakata et al, 2009;Sasaki et al, 2004;Tai et al, 2009). Shh plays multiple essential roles during embryogenesis.…”

“…The latter include recto-anal atresia, recto-urinary or recto-vaginal fistulae and abnormalities of the bladder outflow tract. Animal models have been described for caudal regression or related syndromes such as ano-rectal malformations (ARMs) and were found to involve sonic hedgehog (Mo et al, 2001), retinoic acid (RA) (Padmanabhan, 1998) and the non canonical Wnt5a (Nakata et al, 2009;Tai et al, 2009). A role for Gdf11 and its associated pro-protein convertase Pcsk5 has also been suggested, as inactivating the latter causes the VACTERL-like phenotype (Szumska et al, 2008), which comprises vertebral and ano-rectal anomalies.…”

The role of signalling pathways in urogenital ridge differentiation

“…3.4). Together with a previous report that Wnt5a is expressed in the mesenchyme surrounding the cloacal epithelium and in the posterior tail bud (Nakata et al, 2009;, it is likely that Wnt5a could signal to the WD during migration. …”

“…In two mouse models of anorectal malformation, the all-trans RA-treated mouse and the Dartsforth short tail mouse, Wnt5a expression is down-regulated in the mesenchyme surrounding the cloacal plate, suggesting that Wnt5a may function in cloacal development (Nakata et al, 2009). …”