Girard Beatrice A, Lelievre Vincent, Braas Karen M, Razinia Tannaz, Vizzard Margaret A, Ioffe Yevgeniya, El Meskini Rajaa, Ronnett Gabriele V, Waschek James A, May Victor
Department of Anatomy, University of Vermont College of Medicine, Burlington, 05405, USA.
J Neurochem. 2006 Oct;99(2):499-513. doi: 10.1111/j.1471-4159.2006.04112.x.
Pituitary adenylate cyclase-activating polypeptide (PACAP) and vasoactive intestinal peptide (VIP) are closely related neurotrophic peptides of the secretin/glucagon family. The two peptides are derived from a common ancestral gene and share many functional attributes in neuronal development/regeneration which occur not only from overlapping receptor subtype signaling but also through common mechanisms regulating their expression. Although PACAP or VIP null mice have been generated for study, it is unclear whether the expression of the complementary peptide or their receptor systems are altered in a compensatory manner during nervous system development. By radioimmunoassay and quantitative PCR measurements, we first show that PACAP and VIP have very different temporal patterns of expression in developing postnatal mouse brain. In wild-type animals, PACAP transcript and peptide levels increased rapidly 2- and 5-fold, respectively, within 1 week of age. These levels at 1 week of age were maintained through adulthood. VIP transcript and peptide levels, by contrast, increased 25- and 50-fold, respectively, over a later time course. In parallel studies of development, there were no apparent compensatory increases in brain VIP expression in the PACAP knockout animals, PACAP expression in the VIP-deficient animals, or receptor mRNA levels in either genotype. To the contrary, there was evidence for developmental delays in the expression of peptide and receptor transcripts in the knockout animals. A series of behavioral and neurological tests demonstrated differences between the knockout genotypes, revealing some functional distinctions between the two genes. These results suggest that the PACAP and VIP have evolved to possess distinct biological activities and intimate that the respective knockout phenotypes represent deficits unmitigated by the actions of the complementary related peptide.
垂体腺苷酸环化酶激活多肽（PACAP）和血管活性肠肽（VIP）是促胰液素/胰高血糖素家族中密切相关的神经营养肽。这两种肽源自一个共同的祖先基因，在神经元发育/再生过程中具有许多功能特性，这些特性不仅源于重叠的受体亚型信号传导，还通过调节它们表达的共同机制。尽管已经产生了PACAP或VIP基因敲除小鼠用于研究，但尚不清楚在神经系统发育过程中，互补肽或其受体系统的表达是否以补偿方式发生改变。通过放射免疫测定和定量PCR测量，我们首先表明PACAP和VIP在出生后发育的小鼠脑中具有非常不同的表达时间模式。在野生型动物中，PACAP转录本和肽水平在出生后1周内分别迅速增加了2倍和5倍。这些1周龄时的水平在成年期一直保持。相比之下，VIP转录本和肽水平在较晚的时间过程中分别增加了25倍和50倍。在平行的发育研究中，PACAP基因敲除动物的脑VIP表达、VIP缺陷动物的PACAP表达或任一基因型的受体mRNA水平均无明显的补偿性增加。相反，有证据表明基因敲除动物中肽和受体转录本的表达存在发育延迟。一系列行为和神经学测试表明基因敲除基因型之间存在差异，揭示了这两个基因之间的一些功能区别。这些结果表明，PACAP和VIP已经进化为具有不同的生物学活性，并暗示各自的基因敲除表型代表了未被互补相关肽的作用所减轻的缺陷。
