Functional Synergy between Cholecystokinin Receptors CCKAR and CCKBR in Mammalian Brain Development

Cholecystokinin (CCK), a peptide hormone and one of the most abundant neuropeptides in vertebrate brain, mediates its actions via two G-protein coupled receptors, CCKAR and CCKBR, respectively active in peripheral organs and the central nervous system. Here, we demonstrate that the CCK receptors have a dynamic and largely reciprocal expression in embryonic and postnatal brain. Using compound homozygous mutant mice lacking the activity of both CCK receptors, we uncover their additive, functionally synergistic effects in brain development and demonstrate that CCK receptor loss leads to abnormalities of cortical development, including defects in the formation of the midline and corpus callosum, and cortical interneuron migration. Using comparative transcriptome analysis of embryonic neocortex, we define the molecular mechanisms underlying these defects. Thus we demonstrate a developmental, hitherto unappreciated, role of the two CCK receptors in mammalian neocortical development.胆囊收缩素（Cholecystokinin, CCK）是一种肽类激素，亦是脊椎动物大脑中含量最为丰富的神经肽之一，其通过两种G蛋白偶联受体（G-protein coupled receptor, GPCR）CCKAR与CCKBR分别在外周器官与中枢神经系统中发挥生理活性。本研究证实，胆囊收缩素受体在胚胎期与出生后脑组织中呈现动态且大致呈反向互补的表达模式。本研究构建了同时缺失两种胆囊收缩素受体活性的复合纯合突变小鼠，并利用该模型揭示了二者在脑发育过程中存在叠加且功能协同的调控效应；同时证实，缺失胆囊收缩素受体会引发皮质发育异常，包括中线结构与胼胝体形成缺陷，以及皮质中间神经元迁移障碍。通过对胚胎新皮层开展比较转录组学分析，本研究明确了上述发育缺陷背后的分子机制。综上，本研究证实了两种胆囊收缩素受体在哺乳动物新皮层发育中具有此前未被认知的发育调控功能。