A Peptidomic Approach to Characterize Peptides Involved in Cerebellar Cortex Development Leads to the Identification of the Neurotrophic Effects of Nociceptin

Auriane Corbière,Marie-Laure Walet-Balieu,Philippe Chan,Magali Basille-Dugay,Julie Hardouin,David Vaudry

doi:10.1074/mcp.ra117.000184

Abstract

The cerebellum is a brain structure involved in motor and cognitive functions. The development of the cerebellar cortex (the external part of the cerebellum) is under the control of numerous factors. Among these factors, neuropeptides including PACAP or somatostatin modulate the survival, migration and/or differentiation of cerebellar granule cells. Interestingly, such peptides contributing to cerebellar ontogenesis usually exhibit a specific transient expression profile with a low abundance at birth, a high expression level during the developmental processes, which take place within the first two postnatal weeks in rodents, and a gradual decline toward adulthood. Thus, to identify new peptides transiently expressed in the cerebellum during development, rat cerebella were sampled from birth to adulthood, and analyzed by a semi-quantitative peptidomic approach. A total of 33 peptides were found to be expressed in the cerebellum. Among these 33 peptides, 8 had a clear differential expression pattern during development, 4 of them i.e. cerebellin 2, nociceptin, somatostatin and VGF [353-372], exhibiting a high expression level during the first two postnatal weeks followed by a significative decrease at adulthood. A focus by a genomic approach on nociceptin, confirmed that its precursor mRNA is transiently expressed during the first week of life in granule neurons within the internal granule cell layer of the cerebellum, and showed that the nociceptin receptor is also actively expressed between P8 and P16 by the same neurons. Finally, functional studies revealed a new role for nociceptin, acting as a neurotrophic peptide able to promote the survival and differentiation of developing cerebellar granule neurons.

Highlights

During brain development, neurons originating from germinative zones migrate and establish synaptic connections to generate organized structures and functional networks
In rodents, during the first two postnatal weeks, immature neurons generated in a secondary germinative zone, i.e. the external granule cell layer (EGL)1, migrate along the radial processes of glial cells through the molecular layer (ML) to reach their destination within the internal granule cell layer (IGL; [1])
In the postnatal developing cerebellar cortex, all these processes are under the signaling of various molecules, including growth factors, chemokines, neurotransmitters and/or neuropeptides, which are expressed in a specific spatial and temporal-dependent manner

Summary

Introduction

Neurons originating from germinative zones migrate and establish synaptic connections to generate organized structures and functional networks This developmental process involves numerous factors which modulate cell proliferation, migration, differentiation and survival. C-X-C motif chemokine ligand 14 (CXCL14) is transiently expressed in the cerebellum between P1 and P8 [13], PACAP expression increases from birth to P14 and decreases [14], and somatostatin is actively expressed from birth to P21 [15, 16] These observations suggest that factors, notably peptides, displaying an increased expression during the developmental period (i.e. during the first 2 postnatal weeks in rodents) and a subsequent decline of expression toward adulthood are expected to play a key role in cerebellar development. The aim of the present study was to identify, through omics approaches, peptides exhibiting a transient profile of expression and to subsequently characterize their putative functions

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