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.