Gamma-protocadherins regulate the functional integrity of hypothalamic feeding circuitry in mice.
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.
Su
Hong
H
Department of Biochemistry, Molecular Biology, and Cell Biology, Northwestern University, 2205 Tech Drive, Hogan 2-100, Evanston, IL 60208-3500, USA.
Marcheva
Biliana
B
Meng
Shuxia
S
Liang
Fengxia A
FA
Kohsaka
Akira
A
Kobayashi
Yumiko
Y
Xu
Allison W
AW
Bass
Joseph
J
Wang
Xiaozhong
X
D000818:Animals; D000070585:Cadherin Related Proteins; D015820:Cadherins / Q000235:genetics / Q000502:physiology*; D019070:Cell Lineage; D004734:Energy Metabolism; D005247:Feeding Behavior / Q000502:physiology*; D007031:Hypothalamus / Q000166:cytology / Q000502:physiology*; D007150:Immunohistochemistry; D007515:Islets of Langerhans / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D016253:Microscopy, Immunoelectron; D009474:Neurons / Q000166:cytology; D016133:Polymerase Chain Reaction
D000070585:Cadherin Related Proteins; D015820:Cadherins; C464785:Gamma-protocadherins