Abstract
Vascular endothelial growth factor (Vegfa) is essential for promoting the vascularization of the embryonic murine forebrain. In addition, it directly influences neural development, although its role in the forming forebrain is less well elucidated. It was recently suggested that Vegfa may influence the development of GABAergic interneurons, inhibitory cells with crucial signaling roles in cortical neuronal circuits. However, the mechanism by which it affects interneuron development remains unknown. Here we investigated the developmental processes by which Vegfa may influence cortical interneuron development by analyzing transgenic mice that ubiquitously express the Vegfa120 isoform to perturb its signaling gradient. We found that interneurons reach the dorsal cortex at mid phases of corticogenesis despite an aberrant vascular network. Instead, endothelial ablation of Vegfa alters cortical interneuron numbers, their intracortical distribution and spatial proximity to blood vessels. We show for the first time that vascular-secreted guidance factors promote early-migrating interneurons in the intact forebrain in vivo and identify a novel role for vascular-Vegfa in this process.
Highlights
The mammalian embryonic forebrain develops encased by a dense vascular perineural plexus (PNP), which gives rise to a molecularly and anatomically distinct periventricular plexus (PVP) that invades the basal ganglia primordium at the onset of neurogenesis (Vasudevan et al 2008; Marin-Padilla and Knopman 2011)
Interneurons migrating along the deep migratory stream at the level of the subventricular/ lower intermediate zone (SVZ/LIZ) were located close to Vascular endothelial growth factor (Vegfa) expression in the dorsal ventricular zone (VZ), with the superficial migratory stream located below the Vegfa-expressing meninges (Fig. 1A)
We found that transcript for the Neuropilin 1 receptor (Nrp1) was expressed throughout the medial ganglionic eminence (MGE), with ~40–50% of postmitotic Gad67-gfp+ interneurons expressing Nrp1 throughout all stages of their migration and ~20% of cells expressing the tyrosine-kinase receptor VegfaR1 (Vieira et al 2010) at early, mid, and late stages of their migration (Fig. 1C,E), but not VegfaR2 or VegfaR3 (Supplementary Fig. 2)
Summary
The mammalian embryonic forebrain develops encased by a dense vascular perineural plexus (PNP), which gives rise to a molecularly and anatomically distinct periventricular plexus (PVP) that invades the basal ganglia primordium at the onset of neurogenesis (Vasudevan et al 2008; Marin-Padilla and Knopman 2011). The PVP, for example, was recently shown to regulate the generation of GABAergic interneurons, inhibitory cells with crucial functions in modulating cortical circuitry (Tan et al 2016). Migration and positioning of cortical interneurons are suggested to result in an imbalance of excitatory and inhibitory activity associated with neurological and psychiatric disorders such as epilepsy, autism and schizophrenia (Rubenstein and Merzenich 2003; Murray et al 2014; Lazarus et al 2015; Inan et al 2016). Understanding how the vasculature influences interneuron development is crucial for furthering our knowledge of the pleiotropic origins of neurodevelopmental disorders, especially those that result from an imbalance of excitatory and inhibitory cortical neural signaling
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