Department of Biochemistry, Molecular Biology, and Cell Biology, Northwestern University, 2205 Tech Drive, Hogan 2-100, Evanston, IL 60208-3500, USA.
Dev Biol. 2010 Mar 1;339(1):38-50. doi: 10.1016/j.ydbio.2009.12.010. Epub 2009 Dec 16.
The hypothalamic neuronal circuits that modulate energy homeostasis become mature and functional during early postnatal life. However, the molecular mechanism underlying this developmental process remains largely unknown. Here we use a mouse genetic approach to investigate the role of gamma-protocadherins (Pcdh-gammas) in hypothalamic neuronal circuits. First, we show that rat insulin promoter (RIP)-Cre conditional knockout mice lacking Pcdh-gammas in a broad subset of hypothalamic neurons are obese and hyperphagic. Second, specific deletion of Pcdh-gammas in anorexigenic proopiomelanocortin (POMC) expressing neurons also leads to obesity. Using cell lineage tracing, we show that POMC and RIP-Cre expressing neurons do not overlap but interact with each other in the hypothalamus. Moreover, excitatory synaptic inputs are reduced in Pcdh-gamma deficient POMC neurons. Genetic evidence from both knockout models shows that Pcdh-gammas can regulate POMC neuronal function autonomously and non-autonomously through cell-cell interaction. Taken together, our data demonstrate that Pcdh-gammas regulate the formation and functional integrity of hypothalamic feeding circuitry in mice.
下丘脑调节能量稳态的神经元回路在出生后早期发育成熟并发挥功能。然而，这一发育过程的分子机制在很大程度上仍不清楚。在这里，我们使用一种小鼠遗传方法来研究γ-原钙黏蛋白（Pcdh-gammas）在下丘脑神经元回路中的作用。首先，我们发现广泛缺失下丘脑神经元中 Pcdh-gammas 的大鼠胰岛素启动子（RIP）-Cre 条件性敲除小鼠肥胖且过度摄食。其次，特异性缺失厌食性 proopiomelanocortin（POMC）表达神经元中的 Pcdh-gammas 也会导致肥胖。通过细胞谱系追踪，我们发现 POMC 和 RIP-Cre 表达神经元不重叠，但在下丘脑相互作用。此外，Pcdh-gamma 缺失的 POMC 神经元中的兴奋性突触输入减少。来自两种敲除模型的遗传证据表明，Pcdh-gammas 可以通过细胞-细胞相互作用自主和非自主地调节 POMC 神经元功能。总之，我们的数据表明 Pcdh-gammas 调节了小鼠下丘脑摄食回路的形成和功能完整性。
