Reproductive Defects in the Clock Mutant Mouse

描述（由申请人提供）：下丘脑内的自我维持分子起搏器允许生物体围绕光-暗循环组织生理和行为。在哺乳动物中，CLOCK蛋白是这种起搏器的重要组成部分。一种在时钟基因中具有显性负突变的小鼠品系在缺乏牵引线索的情况下表现出延长和/或不规律的运动活动，我们最近确定该品系也具有多性生殖缺陷。雌性Clock纯合子小鼠显示黄体生成素（LH）释放改变，月经周期不规则，妊娠中期妊娠失败。在目前的建议中，我们假设发情周期和妊娠缺陷都是由于中央起搏器分别向负责控制LH和催乳素释放的神经元输出的改变。我们建议确定这些神经元的昼夜节律输出信号的性质，并通过操纵野生型和突变动物的候选输出信号来验证这一假设。

DESCRIPTION (provided by applicant): A self-sustaining molecular pacemaker within the hypothalamus allows organisms to organize physiology and behavior around the light-dark cycle. In mammals, the CLOCK protein is an essential component of this pacemaker. A mouse strain with a dominant negative mutation in the Clock gene displays lengthened and/or arrhythmic locomotor activity in the absence of entraining cues, and we have recently determined that this strain also has pleiotropic reproductive defects. Female Clock homozygous mice display altered luteinizing hormone (LH) release irregular estrous cycles, and mid-gestational pregnancy failure. In the present proposal, we hypothesize that both the estrous cyclicity and gestational defects are due to altered output from the central pacemaker to the neurons responsible for controlling LH and prolactin release, respectively. We propose to identify the nature of the circadian output signal to these neurons, and to test this hypothesis by manipulating the candidate output signal in wild type and mutant animals.