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Neuro-vascular communication is essential to synchronize central nervous system development. Here, we identify angiopoietin/Tie2 as a neuro-vascular signaling axis involved in regulating dendritic morphogenesis of Purkinje cells (PCs). We show that in the developing cerebellum Tie2 expression is not restricted to blood vessels, but it is also present in PCs. Its ligands angiopoietin-1 (Ang1) and angiopoietin-2 (Ang2) are expressed in neural cells and endothelial cells (ECs), respectively. PC-specific deletion of Tie2 results in reduced dendritic arborization, which is recapitulated in neural-specific Ang1-knockout and Ang2 full-knockout mice. Mechanistically, RNA sequencing reveals that Tie2-deficient PCs present alterations in gene expression of multiple genes involved in cytoskeleton organization, dendritic formation, growth, and branching. Functionally, mice with deletion of Tie2 in PCs present alterations in PC network functionality. Altogether, our data propose Ang/Tie2 signaling as a mediator of intercellular communication between neural cells, ECs, and PCs, required for proper PC dendritic morphogenesis and function.

Angiogenesis and neurogenesis are tightly coupled during embryonic brain development. However, little is known about how these two processes interact. We show that nascent blood vessels actively contact dividing neural stem cells by endothelial filopodia in the ventricular zone (VZ) of the murine ventral telencephalon; this association is conserved in the human ventral VZ. Using mouse mutants with altered vascular filopodia density, we show that this interaction leads to prolonged cell cycle of apical neural progenitors (ANPs) and favors early neuronal differentiation. Interestingly, pharmacological experiments reveal that ANPs induce vascular filopodia formation by upregulating vascular endothelial growth factor (VEGF)-A in a cell-cycle-dependent manner. This mutual relationship between vascular filopodia and ANPs works as a self-regulatory system that senses ANP proliferation rates and rapidly adjusts neuronal production levels. Our findings indicate a function of vascular filopodia in fine-tuning neural stem cell behavior, which is the basis for proper brain development.

Summary: Palmitoylation is a reversible post-translational lipid modification that facilitates vesicular transport and subcellular localization of modified proteins. This process is catalyzed by ZDHHC enzymes that are implicated in several neurological and neurodevelopmental disorders. Loss-of-function mutations in ZDHHC9 have been identified in patients with X-linked intellectual disability (XLID) and associated with increased epilepsy risk. Loss of Zdhhc9 function in hippocampal cultures leads to shorter dendritic arbors and fewer inhibitory synapses, altering the ratio of excitatory-to-inhibitory inputs formed onto Zdhhc9-deficient cells. While Zdhhc9 promotes dendrite outgrowth through the palmitoylation of the GTPase Ras, it promotes inhibitory synapse formation through the palmitoylation of another GTPase, TC10. Zdhhc9 knockout mice exhibit seizure-like activity together with increased frequency and amplitude of both spontaneous and miniature excitatory and inhibitory postsynaptic currents. These findings present a plausible mechanism for how the loss of ZDHHC9 function may contribute to XLID and epilepsy. : Shimell et al. demonstrate that the palmitoylating enzyme Zdhhc9 controls dendritic growth and maintains excitatory/inhibitory synapse balance through distinct substrates. Loss of Zdhhc9 increases network excitability and seizure activity in accordance with Zdhhc9’s association with X-linked intellectual disability and epilepsy. Keywords: Zdhhc9, palmitoylation, neuron morphology, synapse, hippocampal culture, X-linked intellectual disability, dendrite growth, dendrite retraction, Ras GTPase, TC10 GTPase, epilepsy