Cerebellar cortical-layer-specific control of neuronal migration by pituitary adenylate cyclase-activating polypeptide

Abstract

Migration of immature neurons is essential for forming the cortical layers and nuclei. Impairment of migration results in aberrant neuronal cytoarchitecture, which leads to various neurological disorders. Neurons alter the mode, tempo and rate of migration when they translocate through different cortical layers, but little is known about the mechanisms underlying this process. Here we show that endogenous pituitary adenylate cyclase-activating polypeptide (PACAP) has short-term and cortical-layer-specific effects on granule cell migration in the early postnatal mouse cerebellum. Application of exogenous PACAP significantly slowed the migration of isolated granule cells and shortened the leading process in the microexplant cultures of the postnatal day (P)0-3 cerebella. Interestingly, in the cerebellar slices of P10 mice, application of exogenous PACAP significantly inhibited granule cell migration in the external granular layer (EGL) and molecular layer (ML), but failed to alter the movement in the Purkinje cell layer (PCL) and internal granular layer (IGL). In contrast, application of PACAP antagonist accelerated granule cell migration in the PCL, but did not change the movement in the EGL, ML and IGL. Inhibition of the cAMP signaling and the activity of phospholipase C significantly reduced the effects of exogenous PACAP on granule cell migration. The PACAP action on granule cell migration was transient, and lasted for approximately 2 h. The duration of PACAP action on granule cell migration was determined by the desensitization of its receptors and prolonged by inhibiting the protein kinase C. Endogenous PACAP was present sporadically in the bottom of the ML, intensively in the PCL, and throughout the IGL. Collectively, these results indicated that PACAP acts on granule cell migration as "a brake (stop signal) for cell movement." Furthermore, these results suggest that endogenous PACAP slows granule cell migration when the cells enter the PACAP-rich PCL, and 2 h later the desensitization of PACAP receptors allows the cells to accelerate the rate of migration and to actively move within the PACAP-rich IGL. Therefore, endogenous PACAP may provide a cue that regulates granule cell migration in a cerebellar cortical-layer-specific manner.

Phosphorylation of Doublecortin by Protein Kinase A Orchestrates Microtubule and Actin Dynamics to Promote Neuronal Progenitor Cell Migration

“…1H. In contrast to our results, previous reports showed that PACAP inhibits the migration of immature granule neurons in the Purkinje cell layer at the postnatal stage (43,44). On the other hand, it has been reported that a high concentration of PACAP induces G q signaling (45), and G q signaling induced by the endothelin receptor inhibits the migration of NPCs (9).…”

Intrinsic and Extrinsic Mechanisms Control the Termination of Cortical Interneuron Migration

“…For example, isolated granule cells in cerebellar microexplant cultures slow, eventually becoming stationary in culture over a time course that is similar to their in vivo development (Yacubova and Komuro, 2002; see also Trenkner et al, 1984). Alternatively, extrinsic factors may have a vital role, as several secreted molecules have been shown to suppress or promote neuron motility (Powell et al, 2001;Polleux et al, 2002;Pozas and Ibáñez, 2005;Cameron et al, 2007;Lysko et al, 2011).…”

Light stimuli control neuronal migration by altering of insulin-like growth factor 1 (IGF-1) signaling

“…It became apparent that granule cell migration is controlled by the orchestrated activity of multiple molecular events at the right time and right place, including pathway selection, activation of specific receptors and channels, and assembly and disassembly of cytoskeletal components (18)(19)(20)(21)(22). However, the question of how natural environmental stimuli are involved in controlling granule cell migration has been poorly understood.…”