The Protein Tyrosine Phosphatase Receptor Delta Regulates Developmental Neurogenesis.,Cell Reports

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The Protein Tyrosine Phosphatase Receptor Delta Regulates Developmental Neurogenesis.
Cell Reports ( IF 7.5 ) Pub Date : 2020-01-07 , DOI: 10.1016/j.celrep.2019.11.033
Hideaki Tomita ₁ , Francisca Cornejo ₂ , Begoña Aranda-Pino ₂ , Cameron L Woodard ₁ , Constanza C Rioseco ₁ , Benjamin G Neel ₃ , Alejandra R Alvarez ₄ , David R Kaplan ₅ , Freda D Miller ₆ , Gonzalo I Cancino ₇

Affiliation

Program in Neurosciences and Mental Health, Hospital for Sick Children, Toronto M5G 1X8, ON, Canada.
Center for Integrative Biology, Facultad de Ciencias, Universidad Mayor, Santiago 8580745, Chile.
Laura and Isaac Perlmutter Cancer Center, New York University Langone Health, New York, NY 10016, USA.
Departamento de Biología Celular y Molecular, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago 8331010, Chile.
Program in Neurosciences and Mental Health, Hospital for Sick Children, Toronto M5G 1X8, ON, Canada; Institute of Medical Science, University of Toronto, Toronto M5S 1A8, ON, Canada; Department of Molecular Genetics, University of Toronto, Toronto M5S 1A8, ON, Canada.
Program in Neurosciences and Mental Health, Hospital for Sick Children, Toronto M5G 1X8, ON, Canada; Institute of Medical Science, University of Toronto, Toronto M5S 1A8, ON, Canada; Department of Molecular Genetics, University of Toronto, Toronto M5S 1A8, ON, Canada; Department of Physiology, University of Toronto, Toronto M5S 1A8, ON, Canada.
Program in Neurosciences and Mental Health, Hospital for Sick Children, Toronto M5G 1X8, ON, Canada; Center for Integrative Biology, Facultad de Ciencias, Universidad Mayor, Santiago 8580745, Chile.

PTPRD is a receptor protein tyrosine phosphatase that is genetically associated with neurodevelopmental disorders. Here, we asked whether Ptprd mutations cause aberrant neural development by perturbing neurogenesis in the murine cortex. We show that loss of Ptprd causes increases in neurogenic transit-amplifying intermediate progenitor cells and cortical neurons and perturbations in neuronal localization. These effects are intrinsic to neural precursor cells since acute Ptprd knockdown causes similar perturbations. PTPRD mediates these effects by dephosphorylating receptor tyrosine kinases, including TrkB and PDGFRβ, and loss of Ptprd causes the hyperactivation of TrkB and PDGFRβ and their downstream MEK-ERK signaling pathway in neural precursor cells. Moreover, inhibition of aberrant TrkB or MEK activation rescues the increased neurogenesis caused by knockdown or homozygous loss of Ptprd. These results suggest that PTPRD regulates receptor tyrosine kinases to ensure appropriate numbers of intermediate progenitor cells and neurons, suggesting a mechanism for its genetic association with neurodevelopmental disorders.

中文翻译：

蛋白质酪氨酸磷酸酶受体Delta调节发育神经发生。

PTPRD是一种受体蛋白酪氨酸磷酸酶，在遗传上与神经发育障碍有关。在这里，我们问Ptprd突变是否会通过扰动鼠皮层的神经发生而引起异常的神经发育。我们表明，Ptprd的损失会导致神经源性转运放大中间祖细胞和皮层神经元的增加以及神经元定位的扰动。这些作用是神经前体细胞固有的，因为急性Ptprd击倒会引起类似的扰动。PTPRD通过使包括TrkB和PDGFRβ在内的受体酪氨酸激酶去磷酸化来介导这些作用，而Ptprd的缺失会导致TrkB和PDGFRβ的过度活化及其在神经前体细胞中的下游MEK-ERK信号通路。此外，抑制异常的TrkB或MEK激活可挽救Ptprd的敲除或纯合损失所引起的神经发生增加。这些结果表明PTPRD调节受体酪氨酸激酶，以确保适当数量的中间祖细胞和神经元，提示其与神经发育障碍的遗传关联的机制。

更新日期：2020-01-07

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