Cell Reports
Volume 30, Issue 1, 7 January 2020, Pages 215-228.e5
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Article
The Protein Tyrosine Phosphatase Receptor Delta Regulates Developmental Neurogenesis

https://doi.org/10.1016/j.celrep.2019.11.033Get rights and content
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Highlights

  • PTPRD knockdown or knockout induces aberrant increased neurogenesis

  • PTPRD null mice have more intermediate progenitors and cortical neurons

  • PTPRD regulates neurogenesis by modulating RTK-MEK-ERK pathway activity

  • Decreasing MEK/ERK activity or TrkB rescues the perturbations in neurogenesis

Summary

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.

Keywords

PTPRD
TrkB
PDGFRβ
MEK
ERK
neural precursor cells
intermediate progenitors
neurogenesis
cortical development
autism spectrum disorders

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These authors contributed equally

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