Noncompensation in peptide/receptor gene expression and distinct behavioral phenotypes in VIP- and PACAP-deficient mice
Noncompensation in peptide/receptor gene expression and distinct behavioral phenotypes in VIP- and PACAP-deficient mice
复制标题
DOI：
10.1111/j.1471-4159.2006.04112.x
复制
发表时间：
2006-10-01
影响因子：
4.7
通讯作者：
May, Victor
中科院分区：
文献类型：
--
作者：
Girard, Beatrice A.;Lelievre, Vincent;May, Victor
腺苷酸环化酶激活肽（PACAP）和血管活性肠肽（VIP）是分泌素/胰高血糖素家族中密切相关的神经营养肽。这两种肽来源于共同的祖先基因，并且在神经元发育/再生中具有许多功能属性，这些功能属性不仅发生在重叠的受体亚型信号传导中，而且还通过共同的机制调节它们的表达。尽管已经产生了PACAP或VIP缺失小鼠用于研究，但尚不清楚在神经系统发育期间互补肽或其受体系统的表达是否以补偿方式改变。通过放射免疫分析和定量PCR测量，我们首先表明，PACAP和VIP有非常不同的时间模式的表达在发育中的出生后小鼠脑。在野生型动物中，PACAP转录物和肽水平在1周龄内分别迅速增加2倍和5倍。1周龄时的这些水平一直维持到成年。相比之下，VIP转录物和肽水平在随后的时间过程中分别增加了25倍和50倍。在发育的平行研究中，PACAP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水平均无明显的代偿性增加。相反，有证据表明，在基因敲除的动物中，肽和受体转录物的表达存在发育延迟。一系列的行为和神经测试证明了敲除基因型之间的差异，揭示了两个基因之间的一些功能差异。这些结果表明，PACAP和VIP已经进化到具有不同的生物活性，并暗示各自的敲除表型代表了互补相关肽的作用无法减轻的缺陷。
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.