Department of Surgery, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, SAR, China.
Department of Obstetrics and Gynecology, Renji Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, China.
Cell Death Differ. 2019 Aug;26(8):1396-1410. doi: 10.1038/s41418-018-0216-2. Epub 2018 Oct 15.
In mammals, urorectal development starts at early embryonic stage, defective urorectal development results in anorectal malformations, which are common congenital developmental defects of the anus and the urethra in newborns. The etiology and embryology of the defects are still largely unknown. Platelet-derived growth factor receptor alpha (Pdgfra) is a cell surface receptor tyrosine kinase, upon binding to its ligands (Pdgfa-d), mediates intracellular signaling and regulates embryonic development. The expression of Pdgfra is tightly regulated in the developing urorectal mesenchyme, and its dysregulation is associated with urorectal defects in animals with urorectal defects. Knockout of Pdgfra induces early embryo lethality which precludes investigation of Pdgfra in urorectal development. To address the temporal requirement of Pdgfra in urorectal development, we conditionally deleted Pdgfra in Pdgfra-expressing tissues using a tamoxifen inducible Cre-loxP approach in mice, examined the urorectal development in Pdgfra conditional knockout (Pdgfra-cKO) embryos. We showed that conditional deletion of Pdgfra in Pdgfra-expressing tissues at E10-E11 caused cloaca septation defect, anteriorly displaced anus, defective urogenital folds development and abnormal urethra tubularization in both male and female mice. Furthermore, we showed that Pdgfra was required for the survival of urorectal mesenchyme, deletion of Pdgfra caused apoptosis in the peri-cloacal, the peri-urethra and the urorectal septum mesenchyme of Pdgfra-cKO mutants, associated with an induction of p53, Ndrg1 and activation of caspase-3 in Pdgfra-cKO embryos. In conclusion, Pdgfra is required for the development and survival of the urorectal mesenchyme in embryo, dysregulated Pdgfra signaling induced urorectal defects in mice resembling human congenital diseases of anorectal malformations and hypospadias. Perturbation of PDGFRA signaling may contribute to anorectal malformations and hypospadias in human.
在哺乳动物中，尿直肠发育始于早期胚胎阶段，尿直肠发育缺陷导致肛门直肠畸形，这是新生儿肛门和尿道常见的先天性发育缺陷。缺陷的病因和胚胎学仍然很大程度上未知。血小板衍生生长因子受体α（Pdgfra）是一种细胞表面受体酪氨酸激酶，与配体（Pdgfa-d）结合后，介导细胞内信号转导并调节胚胎发育。Pdgfra 在发育中的尿直肠间质中的表达受到严格调控，其失调与动物尿直肠缺陷中的尿直肠缺陷有关。Pdgfra 的敲除会导致早期胚胎致死，这使得无法在尿直肠发育中研究 Pdgfra。为了解决 Pdgfra 在尿直肠发育中的时间要求，我们使用他莫昔芬诱导的 Cre-loxP 方法在 Pdgfra 表达组织中条件性缺失 Pdgfra，检查 Pdgfra 条件性敲除（Pdgfra-cKO）胚胎中的尿直肠发育。我们表明，在 E10-E11 时在 Pdgfra 表达组织中条件性缺失 Pdgfra 会导致泄殖腔分隔缺陷、肛门位置异常、泌尿生殖褶发育缺陷和雌雄小鼠异常尿道管化。此外，我们表明 Pdgfra 是尿直肠间质存活所必需的，Pdgfra 的缺失会导致 Pdgfra-cKO 突变体的围泄殖腔、围尿道和尿直肠隔间质细胞凋亡，并导致 Pdgfra-cKO 胚胎中 p53、Ndrg1 的诱导和 caspase-3 的激活。总之，Pdgfra 是胚胎尿直肠间质发育和存活所必需的，失调的 Pdgfra 信号诱导的小鼠尿直肠缺陷类似于人类先天性肛门直肠畸形和尿道下裂疾病。PDGFRA 信号通路的扰动可能导致人类肛门直肠畸形和尿道下裂。
