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SHANK2 mutations have been identified in individuals with neurodevelopmental disorders, including intellectual disability and autism spectrum disorders (ASD). Using CRISPR/Cas9 genome editing, we obtained SH-SY5Y cell lines with frameshift mutations on one or both SHANK2 alleles. We investigated the effects of the different SHANK2 mutations on cell morphology, cell proliferation and differentiation potential during early neuronal differentiation. All mutant cell lines showed impaired neuronal differentiation marker expression. Cells with bi-allelic SHANK2 mutations revealed diminished apoptosis and increased proliferation, as well as decreased neurite outgrowth during early neuronal differentiation. Bi-allelic SHANK2 mutations resulted in an increase in p-AKT levels, suggesting that SHANK2 mutations impair downstream signaling of tyrosine kinase receptors. Additionally, cells with bi-allelic SHANK2 mutations had lower amyloid precursor protein (APP) expression compared to controls, suggesting a molecular link between SHANK2 and APP. Together, we can show that frameshift mutations on one or both SHANK2 alleles lead to an alteration of neuronal differentiation in SH-SY5Y cells, characterized by changes in cell growth and pre- and postsynaptic protein expression. We also provide first evidence that downstream signaling of tyrosine kinase receptors and amyloid precursor protein expression are affected.

Late in neural development, the expression of growth/differentiation factor (GDF) 15 increases in the germinal epithelium of the murine ganglionic eminence (GE), especially in progenitors with characteristics of neural stem cells (NSCs). However, the function of GDF15 in this region is still unknown. We here show that apical progenitors in the E18 GE also express the GDF15 receptor and that ablation of GDF15 promotes proliferation and cell cycle progression of apically and subapically dividing progenitors. A similar phenotype was also observed in the adult ventricular subventricular zone (V-SVZ). At both ages, increased proliferation leads to the transient generation of more neuronal progenitors, which is compensated by cell death, and to a permanent increase in the number of ependymal cells and apical NSCs. We also found that GDF15 receptor-expressing cells display immunoreactivity for the epidermal growth factor receptor (EGFR), which is also involved in progenitor proliferation, and that manipulation of GDF15 affects the expression of EGFR in mutant progenitors. Moreover, our data indicate that EGFR signalling in WT and mutant progenitors relies on distinct transduction modes. However, only exposure to exogenous GDF15, but not to EGF, normalized proliferation and the number of apical progenitors, indicating that alteration in EGFR signalling is not the main mechanism by which GDF15 affects proliferation in the embryonic GE. Taken together, GDF15 directly regulates proliferation of apical progenitors in the developing GE, thereby affecting the number of total ependymal cells and NSCs in this region.