Pituitary adenylyl cyclase-activating polypeptide controls the proliferation of retinal progenitor cells through downregulation of cyclin D1
Pituitary adenylyl cyclase-activating polypeptide controls the proliferation of retinal progenitor cells through downregulation of cyclin D1
复制标题
DOI：
10.1111/j.1460-9568.2010.07286.x
复制
发表时间：
2010-08-01
影响因子：
3.4
通讯作者：
Silveira, Mariana S.
中科院分区：
文献类型：
--
作者：
Njaine, Brian;Martins, Rodrigo A. P.;Silveira, Mariana S.
在视网膜发育过程中，细胞增殖和退出细胞周期必须精确调节，以确保产生适当数量和比例的各种视网膜细胞类型。在此之前，我们发现垂体腺苷酸环化酶激活多肽（PACAP）通过cAMP依赖性蛋白激酶（蛋白激酶A）（PKA）通路在大鼠发育中的视网膜中发挥神经保护作用。在这里，我们表明，PACAP也调节视网膜祖细胞的增殖。PACAP、PACAP特异性受体（PAC 1）以及由PACAP和血管活性肠肽（VIP）激活的受体（VPAC 1和VPAC 2）在大鼠胚胎和出生后视网膜发育过程中表达。用PACAP 38处理视网膜外植体减少了[3 H]胸苷的掺入以及5-溴-2 '-脱氧尿苷阳性和细胞周期蛋白D1阳性细胞的数量。药理学实验表明，PACAP通过激活PAC 1和VPAC以及cAMP-PKA通路来触发这种抗增殖作用。此外，PACAP受体激活降低细胞周期蛋白D1 mRNA和蛋白质含量。总之，数据支持的假设，PACAP是一种细胞外源性调节剂，在视网膜发育过程中具有多种作用，包括调节视网膜祖细胞亚群的增殖。
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 [3H]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.