Pituitary Adenylyl Cyclase-Activating Polypeptide Stimulates DNA Synthesis But Delays Maturation of Oligodendrocyte Progenitors

Abstract

The neuropeptide pituitary adenylyl cyclase-activating peptide (PACAP) and one of its receptors (PAC 1 ) are expressed in embryonic neural tube, where they appear to regulate neurogenesis and patterning. We now show that PAC 1 gene expression is also present in neonatal rats in the ventricular and subventricular zones and in the optic chiasm, areas that are rich in oligodendrocyte (OL) progenitors (OLP). Because actions of PACAP on OLP have not been reported, we examined the effects of PACAP on the proliferation of purified OLP in culture and on myelinogenesis in cerebellar slices. Northern analyses on total RNA from purified glial cell subtypes revealed an abundant 7 kb hybridizing transcript in OLP, which was confirmed to correspond to the PAC 1 receptor by reverse transcription-PCR. The presence of this receptor was also corroborated by radioligand binding and cAMP assay. In cultured OL, receptor density decreased during maturation but was partially counterbalanced by the appearance of sites that bound both PACAP and the related peptide vasoactive intestinal peptide. PACAP increased DNA synthesis in OLP cultures almost twofold and increased the bromodeoxyuridine-labeling index in O4-positive OLP. PACAP treatment also resulted in decreased sulfate incorporation into sulfatide in cultures of differentiating OL. The PACAP effect on sulfatide synthesis was fully reproduced in a cerebellar explant model. These findings indicate that PACAP may act at two stages during OL development to (1) stimulate proliferation and (2) delay maturation and/or myelinogenesis.

Pituitary Adenylyl Cyclase-activating Polypeptide 38 Reduces Astroglial Proliferation by Inhibiting the GTPase RhoA

“…PAC1 receptors are indeed expressed at low density by neocortical astroglial cells (11,(55)(56)(57). PAC1 receptor mRNA was also found in our cells with use of reverse transcriptase-PCR (data not shown).…”

Pituitary adenylate cyclase-activating polypeptide stimulates glial fibrillary acidic protein gene expression in cortical precursor cells by activating Ras and Rap1

“…It is known that PACAP acts on PAC1 receptors expressed in cortical cells, but it exerts different actions depending on their 13 developmental stage. Thus, before birth PACAP promotes neuronal differentiation from early neural precursors (Suh et al, 2001) and astrogliogenesis from late precursors (Nishimoto et al, 2007;Vallejo and Vallejo, 2002), whereas postanally, PACAP regulates the growth and differentiation of oligodendrocyte progenitors (Lee et al, 2001). Therefore the signaling mechanisms on which PACAP acts during cortical development appear to differ in different cell lineages and to be developmentally regulated.…”

Multiple Actions of Pituitary Adenylyl Cyclase Activating Peptide in Nervous System Development and Regeneration

“…Because neurogenesis is nearly complete by birth, this suggests that PACAP might also be involved in gliogenesis. In this respect, PACAP was found to stimulate oligodendrocyte progenitor proliferation and delay myelinogenesis in in vitro models [28]. PAC 1 gene expression is also abundant in postnatal animals in the external granule layer of the developing cerebellum [27], suggesting a role for PACAP in the development of cerebellar granule neurons.…”

“…In vitro studies which investigate the action of PACAP in the neural tube, using cells isolated from E10.5 mouse hindbrain, are described below. PAC 1 gene expression continues to be abundant in the VZ well into the postnatal period [27,28]. Because neurogenesis is nearly complete by birth, this suggests that PACAP might also be involved in gliogenesis.…”