Tbx5 inhibits hedgehog signaling in determination of digit identity
| Autor: | Henghui Cheng, Qiang Fu, Yushu Qin, Duohua Chen, Linglin Xie, Huiting Xu, Menglan Xiang, Ke Zhang |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Heart Defects Congenital Population Limb Deformities Congenital Repressor Apoptosis medicine.disease_cause Heart Septal Defects Atrial 03 medical and health sciences Mice 0302 clinical medicine GLI1 Genetics Transcriptional regulation medicine Limb development Animals Humans Abnormalities Multiple Hedgehog Proteins Upper Extremity Deformities Congenital education Molecular Biology Genetics (clinical) education.field_of_study Mutation biology General Medicine Smoothened Receptor Hedgehog signaling pathway Cell biology Patched-1 Receptor Disease Models Animal 030104 developmental biology Gene Expression Regulation Gene Knockdown Techniques biology.protein General Article Signal transduction T-Box Domain Proteins 030217 neurology & neurosurgery Lower Extremity Deformities Congenital Signal Transduction |
| Zdroj: | Hum Mol Genet |
| Popis: | Dominant TBX5 mutation causes Holt-Oram syndrome (HOS), which is characterized by limb defects in humans, but the underlying mechanistic basis is unclear. We used a mouse model with Tbx5 conditional knockdown in Hh-receiving cells (marked by Gli1+) during E8 to E10.5, a previously established model to study atrial septum defects, which displayed polydactyly or hypodactyly. The results suggested that Tbx5 is required for digit identity in a subset of limb mesenchymal cells. Specifically, Tbx5 deletion in this cell population decreased cell apoptosis and increased the proliferation of handplate mesenchymal cells. Furthermore, Tbx5 was found to negatively regulate the Hh-signaling activity through transcriptional regulation of Ptch1, a known Hh-signaling repressor. Repression of Hh-signaling through Smo co-mutation in Tbx5 heterozygotes rescued the limb defects, thus placing Tbx5 upstream of Hh-signaling in limb defects. This work reveals an important missing component necessary for understanding not only limb development but also the molecular and genetic mechanisms underlying HOS. |
| Databáze: | OpenAIRE |
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