title: Identification of two novel Shank3 transcripts in the developing mouse neocortex.
abstract: SHANK3 is a synaptic scaffolding protein enriched in the post-synaptic density of excitatory synapses. Since several SHANK3 mutations have been identified in a particular phenotypic group of patients with autism spectrum disorder (ASD), SHANK3 is strongly suspected of being involved in the pathogenesis and neuropathology of ASD. Several SHANK3 isoforms are known to be produced in the developing brain, but they have not been fully investigated. Here, we identified two different amino-terminus truncated Shank3 transcripts. One transcript, designated as Shank3c-3, produces an isoform that contains the entire carboxyl-terminus, but the other transcript, designated as Shank3c-4, produces a carboxyl-terminus truncated isoform. During development, expression of the novel Shank3 transcripts increased after birth, transiently decreased at P14 and then gradually increased again thereafter. We also determined that methyl CpG-binding protein 2 (MeCP2) is involved in regulating expression of the novel Shank3 transcripts. MeCP2 is a transcriptional regulator that has been identified as the causative molecule of Rett syndrome, a neurodevelopmental disorder that includes autistic behavior. We demonstrated a difference between the expression of the novel Shank3 transcripts in wild-type mice and Mecp2-deficient mice. These findings suggest that the SHANK3 isoforms may be implicated in the synaptic abnormality in Rett syndrome. SHANK3 is a synaptic scaffolding protein and is suspected of being implicated in the pathogenesis and neuropathology of ASD. We here identified two different amino-terminus truncated Shank3 transcripts, Shank3c-3 and Shank3c-4, expressed from the intron 10 of the Shank3 gene, and also suggested the epigenetic regulation of their expression via methyl CpG-binding protein 2 (MeCP2) that has been identified as the causative molecule of Rett syndrome.
authors.affiliation: Department of Neurochemistry, National Institute of Neuroscience, Kodaira, Tokyo, Japan; Department of Mental Retardation and Birth Defect Research, National Institute of Neuroscience, Kodaira, Tokyo, Japan.
authors.forename: Chikako
authors.initials: C
authors.lastname: Waga
authors.forename: Hirotsugu
authors.initials: H
authors.lastname: Asano
authors.forename: Tomomi
authors.initials: T
authors.lastname: Sanagi
authors.forename: Eri
authors.initials: E
authors.lastname: Suzuki
authors.forename: Yasuko
authors.initials: Y
authors.lastname: Nakamura
authors.forename: Akiko
authors.initials: A
authors.lastname: Tsuchiya
authors.forename: Masayuki
authors.initials: M
authors.lastname: Itoh
authors.forename: Yu-ichi
authors.initials: Y
authors.lastname: Goto
authors.forename: Shinichi
authors.initials: S
authors.lastname: Kohsaka
authors.forename: Shigeo
authors.initials: S
authors.lastname: Uchino
mesh_terms: D000818:Animals; D002460:Cell Line; D018899:CpG Islands; D005260:Female; D006801:Humans; D007438:Introns; D008297:Male; D051783:Methyl-CpG-Binding Protein 2 / Q000235:genetics / Q000378:metabolism; D008745:Methylation; D051379:Mice; D008810:Mice, Inbred C57BL; D008813:Mice, Inbred ICR; D008822:Mice, Transgenic; D008840:Microfilament Proteins; D019579:Neocortex / Q000196:embryology / Q000254:growth & development / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism; D011485:Protein Binding; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D024363:Transcription Initiation Site; D014158:Transcription, Genetic
chemical_list: C497393:Mecp2 protein, mouse; D051783:Methyl-CpG-Binding Protein 2; D008840:Microfilament Proteins; D009419:Nerve Tissue Proteins; D020033:Protein Isoforms; C492356:Shank3 protein, mouse
keywords: DNA methylation; MeCP2; SHANK3; autism spectrum disorder