The Protein Tyrosine Phosphatase Receptor Delta Regulates Developmental Neurogenesis
The Protein Tyrosine Phosphatase Receptor Delta Regulates Developmental Neurogenesis
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DOI：
10.1016/j.celrep.2019.11.033
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发表时间：
2020-01-07
期刊：
影响因子：
8.8
通讯作者：
Cancino, Gonzalo I.
中科院分区：
文献类型：
--
作者：
Tomita, Hideaki;Cornejo, Francisca;Cancino, Gonzalo I.
PTPRD是一种受体蛋白酪氨酸磷酸酶，遗传上与神经发育障碍有关。在这里，我们询问Ptprd突变是否通过干扰小鼠皮层的神经发生而导致异常的神经发育。我们发现Ptprd的缺失导致神经源性转运放大中间祖细胞和皮质神经元的增加以及神经元定位的扰动。这些影响是神经前体细胞固有的，因为急性Ptprd敲低会引起类似的扰动。PTPRD通过去磷酸化受体酪氨酸激酶（包括TrkB和PDGFR β）介导这些作用，PTPRD的缺失导致神经前体细胞中TrkB和PDGFR β及其下游MEK-ERK信号通路的过度激活。此外，抑制异常的TrkB或MEK激活可以挽救由Ptprd敲低或纯合子缺失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机制。
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 PDGFR beta, and loss of Ptprd causes the hyperactivation of TrkB and PDGFR beta 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.