Pituitary adenylyl cyclase‐activating polypeptide controls the proliferation of retinal progenitor cells through downregulation of cyclin D1

Abstract

During retinal development, cell proliferation and exit from the cell cycle must be precisely regulated to ensure the generation of the appropriate numbers and proportions of the various retinal cell types. Previously, we showed that pituitary adenylyl cyclase-activating polypeptide (PACAP) exerts a neuroprotective effect in the developing retina of rats, through the cAMP-cAMP-dependent protein kinase (protein kinase A) (PKA) pathway. Here, we show that PACAP also regulates the proliferation of retinal progenitor cells. PACAP, PACAP-specific receptor (PAC1), and the receptors activated by both PACAP and vasoactive intestinal peptide (VIP), VPAC1 and VPAC2, are expressed during embryonic and postnatal development of the rat retina. Treatment of retinal explants with PACAP38 reduced the incorporation of [(3)H]thymidine as well as the number of 5-bromo-2'-deoxyuridine-positive and cyclin D1-positive cells. Pharmacological experiments indicated that PACAP triggers this antiproliferative effect through the activation of both PAC1 and VPACs, and the cAMP-PKA pathway. In addition, PACAP receptor activation decreased both cyclin D1 mRNA and protein content. Altogether, the data support the hypothesis that PACAP is a cell-extrinsic regulator with multiple roles during retinal development, including the regulation of proliferation in a subpopulation of retinal progenitor cells.

Development-Related Splicing Regulates Pituitary Adenylate Cyclase-Activating Polypeptide (PACAP) Receptors in the Retina

“…15 Among the PAC1 receptor isoforms, the presence of Hop1 transcript has been reported in adult rat retina only, 30 and no quantitative data are available from newborn or developing tissue. In the present study, we not only demonstrated the presence of PAC1 receptors in different developmental stages of the postnatal rat retina but we showed that for quantification of PAC1 receptor expression, the existence of PAC1 receptor isoforms must be taken into account.…”

“…The integration of retinal cells into functional circuits results from temporally overlapping processes (i.e., cell genesis, apoptosis, migration, and synaptogenesis) that are regulated by numerous intrinsic and extrinsic environmental factors. [23][24][25][26][27][28][29] Although the presence of PACAP receptors and their isoforms in the mammalian retina has been described, 15,30 the physiological function of this peptide has not been established, nor has precise quantitative analysis of the PACAP receptor expression in the retina during postnatal development been carried out.…”

“…However, the expression of both the PACAP gene and its receptors during ontogenesis suggests their involvement in developmental processes. [13][14][15] In fact, a number of functional studies have verified that, in the central nervous system, PACAP contributes to cell proliferation, differentiation, apoptosis, and neurite outgrowth. [16][17][18][19] Along with its antiapoptotic effect, PACAP can act as a mitogenic regulator, as well as an antimitogenic regulator.…”

Protective Effects of PACAP in the Retina

“…The expression of the specifi c PAC1 receptor and VPAC receptors has been confi rmed in the developing mammalian retina, including the retinal progenitor cells [ 44 ]. A shift in PAC1 receptor isoform expression (null, hip, hop1, hiphop1) during development might explain the different roles exerted during differentiation of retinal neural elements [ 45 , 46 ].…”

Pituitary Adenylate Cyclase-Activating Peptide (PACAP), a Novel Secretagogue, Regulates Secreted Morphogens in Newborn Rat Retina

“…However, a complex and diverse set of functions associated with PACAP1-38 has been described in the central nervous system, which encompasses neurogenesis, migration, neural differentiation, and synaptic development. [13][14][15][16] The early appearance in embryonic retina (i.e., PAC1 receptors and PACAP1-38 were detected as early as embryonic days 16 and 19, respectively) 17 and sustained postnatal expression of its receptors 18 indicate that PACAP1-38 very well belongs to a large group of soluble factors that orchestrates retinal development. Functional studies revealed an antimitogenic action of PACAP1-38 on progenitor and postmitotic cells of the newborn retina signaling through both PAC1 and VPAC receptors.…”