Abstract
Postnatal development of the cerebellum is critical for its intact function such as motor coordination and has been implicated in the pathogenesis of psychiatric disorders. We previously reported that deprivation of secretin (SCT) from cerebellar Purkinje neurons impaired motor coordination and motor learning function, while leaving the potential role of SCT in cerebellar development to be determined. SCT and its receptor (SCTR) were constitutively expressed in the postnatal cerebellum in a temporal and cell-specific manner. Using a SCT knockout mouse model, we provided direct evidence showing altered developmental patterns of Purkinje cells (PCs) and granular cells (GCs). SCT deprivation reduced the PC density, impaired the PC dendritic formation, induced accelerated GC migration and potentiated cerebellar apoptosis. Furthermore, our results indicated the involvement of protein kinase A (PKA) and extracellular signal regulated kinase (ERK) signaling pathways in SCT-mediated protective effects against neuronal apoptosis. Results of this study illustrated a novel function of SCT in the postnatal development of cerebellum, emphasizing the necessary role of SCT in cerebellar-related functions.
Highlights
The cerebellum has been well-established as the control center for motor coordination and motor learning in mammalian species while there is a growing acceptance for its implication in the cognitive function (Wagner et al, 2017)
Striking features included the remarkably decreased Purkinje cells (PCs) density and dendritic complexity, in addition to an apparently thinner external granular layer (EGL) in Sct−/− mice. The latter was found to result from accelerated migration and increased apoptosis of granular cells (GCs) under SCT deprivation. We provided both in vivo and in vitro evidences revealing that SCT suppressed apoptosis in the postnatal cerebellum via the cAMP/protein kinase A (PKA) and mitogen activated protein kinase (MAPK)/extracellular signal regulated kinase (ERK) signaling pathways
Well-orchestrated regulation of postnatal development is of critical importance for cerebellar function, as disruption of those processes is correlated with neurodevelopmental disorders such as autism spectrum disorder (ASD; Fatemi et al, 2012; Wang et al, 2014) and Joubert syndrome and related disorders (JSRDs; Joubert et al, 1969; Romani et al, 2013)
Summary
The cerebellum has been well-established as the control center for motor coordination and motor learning in mammalian species while there is a growing acceptance for its implication in the cognitive function (Wagner et al, 2017). During postnatal morphogenesis and development, the cerebellum undergoes dramatic changes as neural progenitor cells undergo mitosis, cell fate specification, radial migration, neurite growth and spine formation. Each of these cellular events is governed by both intrinsic determinants and environmental stimuli (reviewed in Leto et al, 2016). The maturation of Purkinje cells (PCs) and the proliferation and migration of granular cells (GCs) are two critical and interacting events among these developmental progresses (reviewed in Marzban et al, 2014). GCs, the most abundant neurons in central nervous system, undergo intensive proliferation within the external granular layer (EGL), followed by inward radial migration and maturation during the first two postnatal weeks (Butts et al, 2014). PCs, on the other hand, form a single lamina at the early postnatal stage, and develop their
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