Project Detail
Interagency Autism Coordinating Committee (IACC) logo
Office of Autism Research Coordination (OARC) logo

Interaction between MEF2 and MECP2 in the pathogenesis of autism spectrum disorders - 1  

Our laboratories have recently shown that the transcription factor myocyte enhancer factor 2C (MEF2C) activates genes that are important in the development of neurons from embryonic stem cells (termed neurogenesis). In addition to neuronal differentiation, we have shown that MEF2C promotes neuronal survival. In contrast, we have also shown that disruption of MEF2C in mouse models causes devastating developmental abnormalities as well as deficits in cognition and anxiety-related behaviors resembling the autism spectrum disorder (ASD) known as Rett syndrome (RTT). Our idea that MEF2C is related to ASD, including RTT, gained support from discoveries made by other laboratories. In one study, MeCP2 protein, whose deficiency causes RTT, directly regulated MEF2C expression. In another study, MEF2 activity was shown to regulate expression of three of the genes that may be causal for ASD in humans. Taken together, the concept is emerging that MEF2 is a key regulator of signaling pathways that play a role in the pathogenesis of ASD. Interestingly, MeCP2 negatively, rather than positively, regulates MEF2C levels. Therefore, MEF2C activity may be hyperactivated in RTT patients who lack MeCP2. Interestingly, it has been shown previously that too much or too little MeCP2 activity results in similar autistic symptoms in humans and in experimental mouse models. It is thus possible that too much or too little MEF2C activity might be hazardous to brain function and thus contribute to autistic behaviors. Our hypothesis and rationale are as follows: MEF2C is important for normal development and proper function of the brain, and is negatively regulated by MeCP2. The loss of MeCP2 in RTT patients leads to hyperactivation of MEF2C, which in turn results in manifestation of the autistic phenotype. The experiments we propose will test whether this hypothesis is correct. In short, we have devised genetic crosses in such a manner that we will generate mutant mice with different gene dosages of MeCP2 and MEF2C. We will then examine their autistic phenotypes to test whether our hypothesis is correct. If our hypothesis proves to be correct, we will next screen for lead compounds in order to develop drugs that regulate MEF2C activity. We hypothesize that some ASDs are caused by hyperactivation of MEF2C, whereas other ASDs involve hypoactivation of MEF2C (as modeled by our creation of a Mef2C knockout mouse that manifests autistic behaviors). Therefore, we will screen for drugs that either enhance or inhibit MEF2C activity. Using human and mouse embryonic stem cells, we will establish cell lines in which we can reliably measure MEF2 activity. We will then screen these cells with a large collection of chemical agents using our Institute's NIH-designated High-Throughput Screening (HTS) Facility. The drugs that pass the primary screen using these cell lines will be forwarded to a secondary screen, in which physiological effects of drugs will be examined in vitro. For example, drugs that enhance MEF2C activity should promote neuronal differentiation from neuronal precursor/stem cells (NSCs), whereas drugs that inhibit MEF2C activity should interfere with this process. Lead drug candidates that pass the secondary screening will be tested for their ability to ameliorate autistic phenotypes in RTT mouse models. These studies represent very basic research, and it will take many years before we are able to develop new drugs that are useful for curing or treating autism. We anticipate, however, that our studies will advance the knowledge of what appears to be a core-signaling pathway involved in the pathogenesis of RTT and other forms of ASD. Using this knowledge, new therapies will be developed. Project Status
ONGOING

2010

Funder Department of Defense
Fiscal Year Funding $0.00
Current Award Period 2009-2011
Project Number AR080062P1
Principal Investigator Lipton, Stuart
Received ARRA Funding? No
Strategic Plan Question Question 4: Which Treatments And Interventions Will Help? (Treatments)
Subcategory Model Systems/Therapeutic Targets
Strategic Plan Objective Green dot: Objective has greater than or equal to the recommended funding. 4SB. Standardize and validate at least 20 model systems (e.g., cellular and/or animal) that replicate features of ASD and will allow identification of specific molecular targets or neural circuits amenable to existing or new interventions by 2012. IACC Recommended Budget: $75,000,000 over 5 years.
Federal or Private? Federal
Institution Burnham Institute
State/Country California
Web Link 1 Interaction between MEF2 and MECP2 in the pathogenesis of autism spectrum disorders - 1 (External web link)
Web Link 2 No URL available.
Web Link 3 No URL available.
New! History/Related Projects Interaction between MEF2 and MECP2 in the pathogenesis of autism spectrum disorders - 1 | $0.00 | 2009 | AR080062P1
Interaction between MEF2 and MECP2 in the pathogenesis of autism spectrum disorders - 1 | $262,845.00 | 2008 | AR080062P1