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ARS Home » Plains Area » Houston, Texas » Children's Nutrition Research Center » Research » Publications at this Location » Publication #231448
Title: Mecp2 deficiency leads to altered Htr2c pre-mRNA editing and HTR2C isoform distribution in mouse hippocampus and cerebellum

Author
item LANDERS, M - BAYLOR COLLEGE MED
item YU, Z - BAYLOR COLLEGE MED
item Van Den Veyver, Ignatia

Submitted to: American Society of Human Genetics
Publication Type: Abstract Only
Publication Acceptance Date: 10/23/2007
Publication Date: 10/23/2007
Citation: Landers, M., Yu, Z., Van Den Veyver, I. 2007. Mecp2 deficiency leads to altered Htr2c pre-mRNA editing and HTR2C isoform distribution in mouse hippocampus and cerebellum [abstract]. In: 57th Annual Meeting of The American Society of Human Genetics, October 23-27, 2007, San Diego, California. p. 159.

Interpretive Summary:

Technical Abstract: Rett Syndrome (RTT) is a neurodevelopmental disorder caused by mutations in MECP2, a methyl-CpG binding protein and transcriptional repressor. CpG methylation plays an important role in genomic imprinting since imprinted genes are regulated by regions of differentially methylated CpGs (or ICs). A well-studied imprinted region is the one on chr 15q11-q13, involved in Prader-Willi (PWS) and Angelman (AS) syndromes, disorders characterized by several degrees of mental and motor retardation. Many AS cases are caused by deletions or mutations of the maternal copy of UBE3A. UBE3A regulation has been linked to a brain-specific paternally expressed antisense transcript (UBE3AAts) in human and mouse. Ube3aATS also serves as host for several types of paternally expressed snoRNAs: MBII13, MBII52, and MBII85. MBII52 has been shown to affect pre-mRNA editing of the serotonin receptor 2C (Htr2c). Combinations of Htr2c editing (sites A,B,E,C,D) result in the expression of up to 24 HTR2C isoforms with different G protein-coupling functions. Since RTT and AS share autism-spectrum disorder features we decided to assess MBII52 expression in a mouse model of RTT. qRT-PCR assays showed no significant differences in MBII52 levels in hippocampus (Hp) and cerebellum (Cb) from P53-P64 Mecp2(-/y) and Mecp2(+/y) mice. We identified, however, higher edited Htr2c mRNA levels over sites A,B, and C in Mecp2(-/y) Hp and lower levels over sites A,B,E, and D in Mecp2(-/y) Cb. Further analysis revealed that hyperediting of Htr2c mRNA in Mecp2(-/y) Hp leads to a 20% increase in the levels of HTR2C INV, VNI, VNV, and VSV isoforms and a 58% decrease of the unedited INI isoform. Also, altered editing levels in Mecp2(-/y) Cb lead to a slight decrease of the INV, VNI, VNV, and VSV isoforms and a 2.5-fold increase of the INI isoform. Since HTR2C edited isoforms display a reduced ability to activate the phospholipase C signalling cascade, our results support a role for the serotonergic pathway in the pathology of RTT.