Abstract
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.
Original language | English (US) |
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Pages (from-to) | 947-958 |
Number of pages | 12 |
Journal | Neuron |
Volume | 59 |
Issue number | 6 |
DOIs | |
State | Published - Sep 25 2008 |
Funding
We are grateful to B. Lowell and J. Elmquist for the gift of Sim1-cre mice; to A. Bird for Mecp2 flox mice; to the Baylor College of Medicine MRDDRC confocal core; to Christina Thaller and the Baylor College of Medicine in situ core; to the Emory University Biomarkers Core Lab for technical assistance; to the CNRC Body Composition Lab for DEXA scans; and to M. Ramocki and other Zoghbi lab members for helpful comments on the manuscript. This work was funded by National Institutes of Health/National Institute of Neurological Disorders and Stroke grant NS057819 (H.Y.Z.), National Institute of Child Health and Human Development Mental Retardation and Developmental Disabilities Research Center HD024064 (H.Y.Z.), the International Rett Syndrome Foundation, Autism Speaks (R.C.S.), and the Simons Foundation. H.Y.Z. is a Howard Hughes Medical Institute investigator.
Keywords
- HUMDISEASE
- MOLNEURO
- SYSNEURO
ASJC Scopus subject areas
- General Neuroscience