Neural conditional ablation of the protein tyrosine phosphatase receptor Delta PTPRD impairs gliogenesis in the developing mouse brain cortex

Abstract

Neurodevelopmental disorders are characterized by alterations in the development of the cerebral cortex, including aberrant changes in the number and function of neural cells. Although neurogenesis is one of the most studied cellular processes in these pathologies, little evidence is known about glial development. Genetic association studies have identified several genes associated with neurodevelopmental disorders. Indeed, variations in the PTPRD gene have been associated with numerous brain disorders, including autism spectrum disorder, restless leg syndrome, and schizophrenia. We previously demonstrated that constitutive loss of PTPRD expression induces significant alterations in cortical neurogenesis, promoting an increase in intermediate progenitors and neurons in mice. However, its role in gliogenesis has not been evaluated. To assess this, we developed a conditional knockout mouse model lacking PTPRD expression in telencephalon cells. Here, we found that the lack of PTPRD in the mouse cortex reduces glial precursors, astrocytes, and oligodendrocytes. According to our results, this decrease in gliogenesis resulted from a reduced number of radial glia cells at gliogenesis onset and a lower gliogenic potential in cortical neural precursors due to less activation of the JAK/STAT pathway and reduced expression of gliogenic genes. Our study shows PTPRD as a regulator of the glial/neuronal balance during cortical neurodevelopment and highlights the importance of studying glial development to understand the etiology of neurodevelopmental diseases.

Loss of protein tyrosine phosphatase receptor delta PTPRD increases the number of cortical neurons, impairs synaptic function and induces autistic-like behaviors in adult mice

“…What accounts for the increase in glutamatergic neurons in adult Ptprd-/- mice? We propose that it is directly related to the increase in Tbr2-positive intermediate precursor cells in these mice during embryogenesis that we previously reported [ 11 , 12 ]. There is abundant evidence that ASD-associated genes exhibit cell cycle changes in neural precursor cells during brain development, culminating in an alteration in the total number of glutamatergic neurons [ 48 ].…”

“…Mutations or aberrant expression of this gene have previously been associated with various neurodevelopmental disorders such as obsessive-compulsive disorder, schizophrenia, and ASD [ 14 ]. In this regard, we reported that Ptprd is a key regulator of mouse embryonic neurogenesis, controlling the numbers of neurogenic intermediate progenitor cells and, ultimately, the number of neonatal cortical neurons [ 11 , 12 ]. Here, we found that the developmental increase of excitatory neurons persisted through adulthood, affecting excitatory synaptic function in the mPFC.…”

“…For morphometric analysis, immunostaining of tissue sections was performed as described [ 11 , 12 , 20 ]. Briefly, brain sections were washed with 1X TBS for immunostaining.…”

“…Gain or loss of expression or activity of genes involved in these processes are associated with the onset of several brain disorders, including autism spectrum disorder (ASD), schizophrenia, bipolar disorder, attention-deficit/hyperactivity disorder (ADHD), and intellectual disability [ 5 – 10 ]. We reported that alterations in the expression of one of these genes, protein tyrosine phosphatase receptor delta (PTPRD), impairs cerebral cortex development in mice [ 11 , 12 ].…”

“…Ptprd acted as a TrkB and PDGFRβ phosphatase, fine tuning kinase activity and preventing their hyperactivation. Loss of Ptprd resulted in aberrantly increased proliferation of neural precursor cells and concomitant mispositioning of their progeny, embryonic and newborn excitatory neurons [ 11 , 12 ]. Ptprd regulation of receptor tyrosine kinases like TrkB thus ensures the generation of appropriate numbers of neural precursor cells and neurons postnatally.…”