Deletion of Mecp2 in Sim1-expressing neurons reveals a critical role for MeCP2 in feeding behavior, aggression, and the response to stress.
Rett Syndrome (RTT) is an autism spectrum disorder caused by mutations in the X-linked gene encoding methyl-CpG binding protein 2 (MeCP2). In order to map the neuroanatomic origins of the complex neuropsychiatric behaviors observed in patients with RTT and to uncover endogenous functions of MeCP2 in the hypothalamus, we removed Mecp2 from Sim1-expressing neurons in the hypothalamus using Cre-loxP technology. Loss of MeCP2 in Sim1-expressing neurons resulted in mice that recapitulated the abnormal physiological stress response that is seen upon MeCP2 dysfunction in the entire brain. Surprisingly, we also uncovered a role for MeCP2 in the regulation of social and feeding behaviors since the Mecp2 conditional knockout (CKO) mice were aggressive, hyperphagic, and obese. This study demonstrates that deleting Mecp2 in a defined brain region is an excellent approach to map the neuronal origins of complex behaviors and provides new insight about the function of MeCP2 in specific neurons.
Fyffe
Sharyl L
SL
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
Neul
Jeff L
JL
Samaco
Rodney C
RC
Chao
Hsiao-Tuan
HT
Ben-Shachar
Shay
S
Moretti
Paolo
P
McGill
Bryan E
BE
Goulding
Evan H
EH
Sullivan
Elinor
E
Tecott
Laurence H
LH
Zoghbi
Huda Y
HY
D000223:Adaptation, Psychological / Q000502:physiology; D050154:Adiposity / Q000235:genetics / Q000502:physiology; D000374:Aggression / Q000502:physiology; D000818:Animals; D001069:Appetite Regulation / Q000235:genetics / Q000502:physiology*; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism*; D005247:Feeding Behavior / Q000502:physiology; D017353:Gene Deletion; D005818:Genetic Engineering; D007031:Hypothalamus / Q000166:cytology / Q000378:metabolism*; D051783:Methyl-CpG-Binding Protein 2 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D009474:Neurons / Q000378:metabolism*; D012097:Repressor Proteins / Q000378:metabolism*; D012919:Social Behavior; D013315:Stress, Psychological / Q000378:metabolism*
D051792:Basic Helix-Loop-Helix Proteins; D051783:Methyl-CpG-Binding Protein 2; D012097:Repressor Proteins; C101750:Sim1 protein, mouse