Neuropeptides shaping the central nervous system development spatiotemporal actions of vip and pacap through complementary signaling pathways anoxia refers to

Excerpt as incredible as it can be, the whole mammalian nervous system is derived from a unique cell that initiates formation of the primordial neuroepithelium. This structure progressively subdivides into distinct regions in a spatiotemporal patterning process governed by small groups of cells called organizers known to release multiple neutralizing factors (for review, see kiecker and lumsden, 2012). Indeed, the dorsal blastopore lip, also known as the spemann organizer, provides the crucial neural plate patterning along its anteroposterior and mediolateral axes. A fully oriented neural tube is obtained with the appearance of secondary and antagonizing organizers that release diffusible morphogenic and/or trophic signaling factors controlling dorsoventral patterning.Anoxia refers to


these phenomena initiate the generation of multiple cell types at the right place and the right time. Those organizer‐derived secreted factors have long been identified, with their respective roles and mechanisms of action studied in great detail. However, tight regulation of these and subsequent events that generate the different neural cell types and incorporate into functional neural networks has been also proposed based on the observed detrimental effects induced by pharmacological treatments and genetic ablation. The present review aims at recapitulating the differential roles of vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase–activating peptide (PACAP) along the progressive development of the central nervous system, with special emphasis on potential therapeutic actions of these molecules in diagnosis, prevention, and treatment of pathologies with neurodevelopmental origins.Anoxia refers to

These two peptides belong to the PACAP/glucagon superfamily of neuropeptides and share very high similarity in both nucleotidic and amino acid sequences. They all present the characteristic signature of the histidyl‐seryl residues at the N‐terminus (sherwood et al., 2000). Originating from gene duplications occurring early in evolution, this family shares a very conserved biosynthesis process whereby inactive prepropeptides are cleaved and secreted into one or two bioactive molecules. In the case of mammalian VIP and PACAP genes, the whole processing gives rise to peptide histidine isoleucine (PHI)/methionine (PHM), which only differ by the single substitution of isoleucine into PHM in human, and VIP or PACAP‐related peptide and PACAP‐38 (the 38‐amino‐acid‐long peptide that can be further shortened to PACAP‐27), respectively.Anoxia refers to

A similar evolution has been proposed for their receptors (ng et al., 2012), together providing a satisfactory explanation for the equal binding affinities of the two neuropeptides for their so‐called VIP‐PACAP receptors. In addition, VIP and PACAP display partial redundancy in their distribution patterns and exert complementary functions from embryonic stages to adulthood (nishizawa et al., 1985; linder et al., 1987; sherwood et al., 2000).

Indeed, VIP and PACAP bind the polyvalent VIP‐PACAP receptors, VPAC1 and VPAC2, which display similar nanomolar affinity for PACAP and VIP (harmar et al., 2012). VPACs belong to the class II family of G protein–coupled receptors (gpcrs) bearing the characteristically large extracellular N‐terminal domain important for ligand recognition and binding (laburthe et al., 2007), anchored by a seven‐transmembrane domain intersected by intra‐ and extracellular loops involved in signal transduction and ligand recognition, respectively.Anoxia refers to the seven‐transmembrane domain extends further to the intracellular C‐terminal domain crucial for activating G protein–dependent signaling that is mainly coupled to adenylate cyclase and phospholipase C (laburthe et al., 2007).

VPAC structure is highly conserved within the species (couvineau and laburthe, 2012) and shares almost 50% homology with PAC1 in rats (vaudry et al., 2009). Indeed, vpacs are also characterized as type II receptors for PACAP. However, PACAP binds another receptor (the type I PACAP receptor), PAC1, which may also bind maxadilan (an unrelated peptide identified in sand fly) and VIP but with less affinity (gottschal et al., 1990; moro and lerner, 1997).