Abstract
Anorectal malformations (ARMs) are relatively common congenital abnormalities, but their pathogenesis is poorly understood. Previous gene knockout studies indicated that the signalling pathway mediated by the retinoic acid receptors (RAR) is instrumental to the formation of the anorectal canal and of various urogenital structures. Here, we show that simultaneous ablation of the three RARs in the mouse embryo results in a spectrum of malformations of the pelvic organs in which anorectal and urinary bladder ageneses are consistently associated. We found that these ageneses could be accounted for by defects in the processes of growth and migration of the cloaca, the embryonic structure from which the anorectal canal and urinary bladder originate. We further show that these defects are preceded by a failure of the lateral shift of the umbilical arteries and propose vascular abnormalities as a possible cause of ARM. Through the comparisons of these phenotypes with those of other mutant mice and of human patients, we would like to suggest that morphological data may provide a solid base to test molecular as well as clinical hypotheses.
Highlights
Published: 28 June 2021Anorectal malformations (ARM) are a group of diverse congenital defects characterised by an abnormal termination of the rectum, with a clinical spectrum ranging from anal stenosis to persistent cloaca
The cloaca is a transient dilation of the embryonic hindgut which, in placental mammals, undergoes a complex process of morphogenesis leading to its division into two separate compartments, the urogenital sinus (UGS), at the origin of the urinary bladder and proximal part of the urethra, and the anorectal canal [3,4,5,6]
They provide evidence for a function of retinoic acid receptors (RAR) in vascular remodelling, and support the possibility that vascular defects during the period of cloacal development could be involved in the pathogenesis of ARM
Summary
Anorectal malformations (ARM) are a group of diverse congenital defects characterised by an abnormal termination of the rectum, with a clinical spectrum ranging from anal stenosis to persistent cloaca. Because RARs exert redundant functions in a variety of developing systems, we decided to completely impair ATRA signalling through ablation of all three RAR-coding genes This was not possible by associating Rara, Rarb and Rarg KO alleles in a single mouse, because Rara− /− Rarg− /− ;Rarb+/ − KO embryos do not develop beyond E8.5, precluding any analysis of organogenesis [14]. Our results indicate that RAR signalling has important functions in the processes of growth and posterior migration of the cloaca They provide evidence for a function of RARs in vascular remodelling, and support the possibility that vascular defects during the period of cloacal development could be involved in the pathogenesis of ARM
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