VEGF is required for dendritogenesis of newly born olfactory bulb interneurons

Abstract

SUMMARYThe angiogenic factor vascular endothelial growth factor A (VEGF) has been shown to have a role in neurogenesis, but how it affects adult neurogenesis is not fully understood. To delineate a role for VEGF in successive stages of olfactory bulb (OB) neurogenesis, we used a conditional transgenic system to suppress VEGF signaling at the adult mouse sub-ventricular zone (SVZ), rostral migratory stream (RMS) and OB, which constitute the respective sites of birth, the migration route, and sites where newly born interneurons mature and integrate within the existing OB circuitry. Following the development of fluorescently tagged adultborn neurons, we show that sequestration of VEGF that is constitutively expressed by distinct types of resident OB neurons greatly impaired dendrite development in incoming SVZ-born neurons. This was evidenced by reduced dendritic spine density of granule cells and significantly shorter and less branched dendrites in periglomerular neurons. Notably, the vasculature and perfusion of the SVZ, RMS and OB were not adversely affected when VEGF suppression was delayed until after birth, thus uncoupling the effect of VEGF on dendritogenesis from its known role in vascular maintenance. Furthermore, a requirement for VEGF was specific to newly born neurons, as already established OB neurons were not damaged by VEGF inhibition. This study thus uncovered a surprising perfusion-independent role of VEGF in the adult brain, namely, an essential role in the maturation of adult-born neurons.

Cyr61, a Matricellular Protein, Is Needed for Dendritic Arborization of Hippocampal Neurons

“…For example, CCN5 induces neurite outgrowth in a neuroblastoma Neuro2a cell line in an integrin-dependent manner (51). Licht et al (52) showed that the angiogenic factor VEGF is necessary for the dendritic arbor development of adult-born interneurons that integrate into olfactory bulb circuitry. Another angiogenic protein, angiopoietin-1, was able to induce neurite outgrowth in PC12 cells (53) and increase the dendritic length of CA1 neurons when overexpressed in vivo (54).…”

Roles of Planar Cell Polarity Signaling in Maturation of Neuronal Precursor Cells in the Postnatal Mouse Olfactory Bulb

“…Previous studies identified several extracellular factors involved in the dendritogenesis of SVZ-derived OB interneurons, including GABA [58] and vascular endothelial growth factor (VEGF) [59]. Wnt5a, which likely activates the PCP signaling pathway, increases the neurite complexity of OB interneurons derived from the SVZ [35].…”

Molecular Parallels between Neural and Vascular Development

“…Adult neurogenesis in the SVZ is also unaffected in CaMKII-CRE, loxVegf-a mice, which bear a conditional ablation of VEGF-A expression in neurons, suggesting that the main source of VEGF-A in the brain is not provided by the neurons (Licht et al 2010). In addition, several reports indicate that other members of the VEGF/VEGFR family expressed by neural cells promote neurogenesis and could functionally compensate the absence of VEGF-A.…”

“…The Keshet laboratory used a conditional transgenic system expressing soluble VEGFR-1 (VEGFR-1-Ig) to suppress VEGF signaling in the mouse adult brain within the RMS and the OB (Licht et al 2010) or in the hippocampus (Licht et al 2011). In the OB, VEGF is constitutively expressed by distinct types of resident neurons, and VEGF sequestration by VEGFR1-Ig impairs dendrite development in newborn neurons, as indicated by the reduced dendritic spine density of granule cells and the shorter and less branched dendrites of periglomerular neurons.…”

“…The effect of VEGF on dendritogenesis is independent from its role in vascular maintenance, because only dendritogenesis, but not vasculature and perfusion of the SVZ, RMS, and OB, was modified by VEGF blockade after birth. The requirement for VEGF is specific to newly born OB neurons, because dendrites of already established neurons are not damaged by VEGF sequestration (Licht et al 2010). In the hippocampus, VEGF overexpression promoted angiogenesis, neurogenesis, and memory and increased long-term potentiation (LTP) responses, and thus plasticity, in the dentate gyrus in vivo.…”