VEGF signalling controls GnRH neuron survival via NRP1 independently of KDR and blood vessels

Abstract

Gonadotropin-releasing hormone (GnRH) neurons are neuroendocrine cells that are born in the nasal placode during embryonic development and migrate through the nose and forebrain to the hypothalamus, where they regulate reproduction. Many molecular pathways that guide their migration have been identified, but little is known about the factors that control the survival of the migrating GnRH neurons as they negotiate different environments. We previously reported that the class 3 semaphorin SEMA3A signals through its neuropilin receptors, NRP1 and NRP2, to organise the axons that guide migrating GnRH neurons from their birthplace into the brain. By combining analysis of genetically altered mice with in vitro models, we show here that the alternative neuropilin ligand VEGF164 promotes the survival of migrating GnRH neurons by co-activating the ERK and AKT signalling pathways through NRP1. We also demonstrate that survival signalling relies on neuronal, but not endothelial, NRP1 expression and that it occurs independently of KDR, the main VEGF receptor in blood vessels. Therefore, VEGF164 provides survival signals directly to developing GnRH neurons, independently of its role in blood vessels. Finally, we show that the VEGF164-mediated neuronal survival and SEMA3A-mediated axon guidance cooperate to ensure that migrating GnRH neurons reach the brain. Thus, the loss of both neuropilin ligands leads to an almost complete failure to establish the GnRH neuron system.

Diverse roles for VEGF-A in the nervous system

“…Treatment of immortalised GnRH neurons showed that VEGF164 enhanced survival, but not proliferation, and that the survival pathways involved co-activating phosphoinositide 3-kinase and mitogen-activated protein kinase signalling in an NRP1-dependent fashion (Cariboni et al, 2011). In agreement with the in vitro findings, apoptotic bodies were abundant along the VEGF-A-positive path that is taken by these neurons during embryogenesis as they travel from their birthplace in the nasal cavity to their destination in the hypothalamus (Cariboni et al, 2011). Importantly, this study also showed that mice lacking VEGFR2 in the neural lineage or NRP1 in blood vessels contained normal numbers of these neurons, establishing that VEGF164 signals through NRP1 in a cell-autonomous fashion, independently of vascular VEGF-A signalling or blood vessels.…”

“…The first unequivocal evidence that VEGF-A conveys physiological survival signals in neurons expressing VEGF-A receptors was provided by the finding that mice lacking VEGF164 or NRP1 in the neural lineage contain reduced numbers of GnRH neurons, which are essential for gonad development and fertility ( Fig. 3E) (Cariboni et al, 2011). Treatment of immortalised GnRH neurons showed that VEGF164 enhanced survival, but not proliferation, and that the survival pathways involved co-activating phosphoinositide 3-kinase and mitogen-activated protein kinase signalling in an NRP1-dependent fashion (Cariboni et al, 2011).…”

“…3E) (Cariboni et al, 2011). Treatment of immortalised GnRH neurons showed that VEGF164 enhanced survival, but not proliferation, and that the survival pathways involved co-activating phosphoinositide 3-kinase and mitogen-activated protein kinase signalling in an NRP1-dependent fashion (Cariboni et al, 2011). In agreement with the in vitro findings, apoptotic bodies were abundant along the VEGF-A-positive path that is taken by these neurons during embryogenesis as they travel from their birthplace in the nasal cavity to their destination in the hypothalamus (Cariboni et al, 2011).…”

Changes in granulosa cells' gene expression associated with increased oocyte competence in bovine

“…NRP1 is a VEGFA co-receptor, and the sema domain, immunoglobulin domain (Ig), short basic domain, and secreted (semaphorin) 3A (SEMA3A) receptor (Cariboni et al 2011). Interestingly, VEGFA is lower in Frizzled-4 (FZD4) KO mice associated with an infertile phenotype (failure to become pregnant) (Hsieh et al 2005).…”

Brain Tumor–Induced Angiogenesis: Approaches and Bioassays

“…Cariboni et al were also able to illustrate a KDR and blood vessel independent way via VEGF-NRP-1 interactions [37]. Its isoform, neuropi-lin-2 receptor probably modulates the affinity of VEGF-C and -D to VEGFR-3 and is thought to be important in lymphangiogenesis [38,39].…”