Caudal developmental defects, including caudal regression, caudal dysgenesis and sirenomelia, are devastating conditions affecting the skeletal, nervous, digestive, reproductive and excretory systems. Defects in mesodermal migration and blood supply to the caudal region have been identified as possible causes of caudal developmental defects, but neither satisfactorily explains the structural malformations in all three germ layers. Here, we describe caudal developmental defects in transmembrane protein 132a (Tmem132a) mutant mice, including skeletal, posterior neural tube closure, genitourinary tract and hindgut defects. We show that, in Tmem132a mutant embryos, visceral endoderm fails to be excluded from the medial region of early hindgut, leading directly to the loss or malformation of cloaca-derived genitourinary and gastrointestinal structures, and indirectly to the neural tube and kidney/ureter defects. We find that TMEM132A mediates intercellular interaction, and physically interacts with planar cell polarity (PCP) regulators CELSR1 and FZD6. Genetically, Tmem132a regulates neural tube closure synergistically with another PCP regulator Vangl2. In summary, we have identified Tmem132a as a new regulator of PCP, and hindgut malformation as the underlying cause of developmental defects in multiple caudal structures.
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http://dx.doi.org/10.1242/dev.201630 | DOI Listing |
Am J Hum Genet
January 2025
Institute of Medical Genetics and Applied Genomics, University of Tübingen, 72076 Tübingen, Germany; Center for Rare Disease, University of Tübingen, 72076 Tübingen, Germany; Genomics for Health in Africa (GHA), Africa-Europe Cluster of Research Excellence (CoRE).
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Key Laboratory of Zoological Systematics and Application, College of Life Sciences, Hebei University, Baoding 071002, China. Electronic address:
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View Article and Find Full Text PDFNat Commun
January 2025
Shanghai Institute of Precision Medicine, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
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January 2025
Department of Anatomy and Neurobiology, Research Center for Sectional and Imaging Anatomy, Shandong Provincial Key Laboratory of Mental Disorder, Shandong Key Laboratory of Digital Human and Clinical Anatomy, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China.
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