Introduction: Second messengers in neural development

The nervous system is probably the tissue that most dramatically changes throughout development. Macroscopically, it transforms itself from a flat neural plate, into the multicellularly layered, lobular, convoluted and tubular morphology of the brain and spinal cord; at the cellular level, it transits from a nonpolarized cuboidal neural plate cell to a morphologically exuberant neuron such as the cerebellar Purkinje cell. These morphological changes are accompanied by changes in cell and tissue functions, which increase in complexity as development progresses. The transformation of the developing nervous system requires a very precise spatiotemporal regulation. How is this complexity achieved and what are the mechanisms that drive this transformation? Second messenger signaling serves to implement the changes in phenotype rapidly and in a spatiotemporally sensitive manner. This special issue includes eight review articles that capture the new advances on the current understanding of second messenger signaling during neural development. Second messengers are recruited by diverse developmental cues. Two reviews in this issue compile studies that demonstrate crucial roles for second messenger signaling in mediating morphogenetic protein actions. Pal and Mukhopadhyay (2014) summarize the key studies that demonstrate the participation of second messengers, chiefly cAMP, Ca, and IP3, in Sonic hedgehog (Shh) signaling pathway. The recent identification of an orphan G-protein coupled receptor, Gpr161, at the primary cilium demonstrated the mechanism by which Shh releases the inhibition that increased cAMP levels and PKA exert on Shh canonical signaling. From morphogenetic proteins to environmental stimuli all utilize second messenger signaling to drive a wide spectrum of developmental processes. For instance, Shh, Wnts and bone morphogenetic proteins modulate Ca-mediated activity in developing neural cells that in turn regulate global transcriptional-dependent events such as neurotransmitter specification or local events like growth cone turning and dendritic outgrowth (Borodinsky et al., 2014). The role of second messenger signaling in neural development is apparent from the very beginning. The Uhl en lab reviews the function of synchronized Ca activity in the regulation of neural progenitor proliferation and neocortical development (Uhl en et al., 2014), which supports the concept of presynaptogenic electrical activity in the developing nervous system. Indeed, spontaneous Ca transients are apparent in migrating immature cerebellar granule cells. In turn these Ca transients are modulated by cAMP and cGMP dynamics and depend on glutamate and IGF1 signaling (Komuro et al., 2014). This review also summarizes the role of altered second messenger signaling in granule cell migration deficits associated with fetal alcohol spectrum disorders and methylmercury intoxication. Once developing neurons migrate they polarize to elaborate functional compartments that will allow them to send signals and receive inputs. Guo and Chen (2014) review the current understanding of the process of axon and dendrite differentiation by focusing on studies that not only investigate the positive and negative feedback mechanisms of second messenger signaling, such as cAMP and phosphoinositide triphosphate, in neuronal polarization but also on the mechanical forces that drive changes in cell shape. They propose a mechanochemical-based model in which cytoskeletal mechanics lead to elaboration of cell protrusions, which in turn limit localization of second messengers and regulate their dynamics, thus breaking neuronal precursor symmetry. Neuronal polarization is followed by the outgrowing of dendrites and axon and its routing towards the appropriate target cells. Two reviews in this issue elaborate on the mechanisms of Ca and cAMP dynamics in growth cone turning and axon guidance. Sutherland and Goodhill (2014) focus on the origin of growth cone Ca elevations and the interdependence between second messengers in the process of axon guidance. They review a mathematical model for attractive and repulsive growth cone turning responses dependent on relative activation of CaMKII and calcineurin, pivotal effectors of Ca 2015 Wiley Periodicals, Inc. Published online 3 February 2015 in Wiley Online Library (wileyonlinelibrary.com). DOI 10.1002/dneu.22269