Abstract
Protein tyrosine phosphatase receptor type Z1 (PTPRZ1) is one of the most abundantly expressed and enriched genes in astrocytes during development, yet its function in astrocytes is unknown. Using an astrocyte-neuron co-culture system, we found that knockdown of Ptprz1 in astrocytes significantly impaired astrocyte branching morphogenesis. To investigate the function of PTPRZ1 in astrocytes during brain development, we generated a Ptprz1 conditional knockout mouse and deleted Ptprz1 from astrocytes postnatally, after the bulk of astrogenesis is complete. At postnatal day 21, we found subtle changes in astrocyte morphology and a reduction in the density of co-localized pre and post synaptic excitatory synapse markers across multiple layers of the visual cortex in both male and female mice, suggesting important functions for astrocytic PTPRZ1 in both astrocyte morphogenesis and synaptogenesis. PTPRZ1 is expressed in several neural cell types, including radial glial stem cells and oligodendrocyte progenitor cells (OPCs), and regulates critical aspects of neurodevelopment, including neurite outgrowth, neuronal differentiation, myelination, and extracellular matrix (ECM) development. Moreover, altered PTPRZ1 expression is associated with schizophrenia and glioblastoma. Therefore, this mouse model is a valuable resource for investigating cell-type-specific PTPRZ1 function in numerous neurodevelopmental and neuropathological mechanisms.
Significance Statement PTPRZ1 is an abundant, astrocyte-enriched protein linked to neurological dysfunction; however, its astrocyte-specific functions are unknown. We generated a Ptprz1 conditional knockout mouse and found that astrocyte-specific deletion of Ptprz1 reduces the density of co-localized excitatory synapse markers in the developing mouse cortex, with mild impact to astrocyte morphology. PTPRZ1 is an emerging therapeutic target for glioblastoma and neurodegeneration. This study provides a new tool to study PTPRZ1 function in neurodevelopment and neuropathology.
Footnotes
We thank Dr. Cagla Eroglu for providing the Ptprz1 floxed mouse line, and the Duke Transgenic Mouse Facility for generating the Ptprz1 floxed mouse line. We thank Amy Stanek for technical assistance in sample processing.
Authors report no conflict of interest
The Baldwin Lab is supported by the NIH, DP2NS136873 to K.T.B. and T32NS007431 to H.E.S and B.C.D. Microscopy was performed at the UNC Neuroscience Microscopy Core (RRID:SCR_019060), supported, in part, by funding from the NIH-NICHD Intellectual and Developmental Disabilities Research Center Support Grant P50 HD103573. The UNC Hooker Imaging Core Facility is supported in part by P30 CA016086 Cancer Center Core Support Grant to the UNC Lineberger Comprehensive Cancer Center. The Leica Stellaris 8 Falcon STED is supported by the NIH Shared Instrumentation Grant 1S10OD030300 to S. Gupton. The BRAIN Initiative Viral Vector Core is supported in part by the NIH U24NS124025 to K. Ritola.
↵*These authors contributed equally
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