Abstract
BackgroundDuring postnatal murine and rodent cerebellar development, cerebellar granule precursors (CGP) gradually stop proliferating as they differentiate after migration to the internal granule layer (IGL). Molecular events that govern this program remain to be fully elucidated. GPR3 belongs to a family of Gs-linked receptors that activate cyclic AMP and are abundantly expressed in the adult brain.Methodology/Principal FindingsTo investigate the role of this orphan receptor in CGP differentiation, we determined that exogenous GPR3 expression in rat cerebellar granule neurons partially antagonized the proliferative effect of Sonic hedgehog (Shh), while endogenous GPR3 inhibition by siRNA stimulated Shh-induced CGP proliferation. In addition, exogenous GPR3 expression in CGPs correlated with increased p27/kip expression, while GPR3 knock-down led to a decrease in p27/kip expression. In wild-type mice, GPR3 expression increased postnatally and its expression was concentrated in the internal granular layer (IGL). In GPR3 −/− mice, the IGL was widened with increased proliferation of CGPs, as measured by bromodeoxyuridine incorporation. Cell cycle kinetics of GPR3-transfected medulloblastoma cells revealed a G0/G1 block, consistent with cell cycle exit.Conclusions/SignificanceThese results thus indicate that GPR3 is a novel antiproliferative mediator of CGPs in the postnatal development of murine cerebellum.
Highlights
In the adult, the cerebellum is organized into distinct layers, each containing specialized neuronal cell populations, positioned there during postnatal development with precise coordination of processes involving cell proliferation, differentiation, and migration
We sought to determine whether GPR3 expression inhibited proliferative signals (Sonic hedgehog- Shh) and/or correlated with antiproliferative markers (p27/kip), known to be important in postnatal cerebellar development
GPR3 is a member of a family of G-protein couple receptors whose activation of PKA and subsequent increase of cyclic AMP level promotes meiotic arrest in the oocyte[38]
Summary
The cerebellum is organized into distinct layers, each containing specialized neuronal cell populations, positioned there during postnatal development with precise coordination of processes involving cell proliferation, differentiation, and migration. In the immediate postnatal period, the outermost layer, the external granule layer (EGL), contains dividing granule neuron progenitors (GNP) These granule cells migrate inwards, guided by Bergmann radial glial fibers through the molecular layer (ML), pass through the Purkinje neuron layer (PL) containing the cell bodies of Purkinje neurons and Bergmann glia and settle into the internal granular layer (IGL) where they exit the cell cycle and terminally differentiate[1,2,3,4,5,6,7,8]. GPR3 belongs to a family of Gs-linked receptors that activate cyclic AMP and are abundantly expressed in the adult brain
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