Department of Biology, Indiana University-Purdue University Indianapolis, Indianapolis, Indiana 46202.
Department of Biology, Indiana University-Purdue University Indianapolis, Indianapolis, Indiana 46202
eNeuro. 2021 Sep 29;8(5). doi: 10.1523/ENEURO.0276-21.2021. Print 2021 Sep-Oct.
The hedgehog signaling pathway is best known for its role in developmental patterning of the neural tube and limb bud. More recently, hedgehog signaling has been recognized for its roles in growth of adult tissues and maintenance of progenitor cell niches. However, the role of hedgehog signaling in fully differentiated cells like neurons in the adult brain is less clear. In mammals, coordination of hedgehog pathway activity relies on primary cilia and patients with ciliopathies such as Bardet-Biedl and Alström syndrome exhibit clinical features clearly attributable to errant hedgehog such as polydactyly. However, these ciliopathies also present with features not clearly associated with hedgehog signaling such as hyperphagia-associated obesity. How hedgehog signaling may contribute to feeding behavior is complex and unclear, but cilia are critical for proper energy homeostasis. Here, we provide a detailed analysis of the expression of core components of the hedgehog signaling pathway in the adult mouse hypothalamus with an emphasis on feeding centers. We show that hedgehog pathway genes continue to be expressed in differentiated neurons important for the regulation of feeding behavior. Furthermore, we demonstrate for the first time that pathway activity is regulated at the transcriptional level by fasting. These data suggest that hedgehog signaling is involved in the proper functioning of brain regions that regulate feeding behavior and that hedgehog pathway dysfunction may play a role in the obesity observed in certain ciliopathies.
刺猬信号通路在神经管和肢芽的发育模式形成中起着至关重要的作用。最近，刺猬信号通路在成人组织的生长和祖细胞龛的维持中的作用也得到了认可。然而，刺猬信号通路在完全分化的细胞中的作用，如成年大脑中的神经元，还不太清楚。在哺乳动物中，刺猬通路活性的协调依赖于初级纤毛，患有纤毛病如 Bardet-Biedl 和 Alström 综合征的患者表现出明显归因于刺猬信号通路异常的临床特征，如多指畸形。然而，这些纤毛病也表现出与刺猬信号通路不明确相关的特征，如与摄食行为相关的肥胖。刺猬信号通路如何影响摄食行为是复杂而不清楚的，但纤毛对于适当的能量平衡是至关重要的。在这里，我们提供了一个详细的分析，在成年小鼠下丘脑的核心组成部分的刺猬信号通路的表达，重点是摄食中心。我们表明，刺猬信号通路基因在调节摄食行为的分化神经元中继续表达。此外，我们首次证明了，在转录水平上，通路活性受禁食调节。这些数据表明，刺猬信号通路参与了调节摄食行为的脑区的正常功能，而刺猬信号通路功能障碍可能在某些纤毛病中观察到的肥胖中起作用。
