期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2014
卷号：111
期号：31
页码：11521-11526
DOI：10.1073/pnas.1411251111
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：SignificanceNeurodegenerative diseases are debilitating conditions that result from degeneration of the nervous system causing symptoms including ataxia and/or dementia. Calmodulin-binding transcription activator 1 (CAMTA1) is a transcription factor enriched in the brain with the highest levels of expression in the cerebellar granular layer and Purkinje cells, midbrain, pons, and hippocampus. When CAMTA1 is deleted from the nervous system of mutant mice, we observe a clear loss of Purkinje cells and reduced cerebellar size. Thus, we conclude that CAMTA1 plays a predominant role in the maturation and survival of cerebellar neurons rather than in the initial development of these cells. The neurological abnormalities associated with CAMTA1-mutant mice allow mechanistic analysis of these abnormalities and disease modeling. Members of the calmodulin-binding transcription activator (CAMTA) family of proteins function as calcium-sensitive regulators of gene expression in multicellular organisms ranging from plants to humans. Here, we show that global or nervous system deletion of CAMTA1 in mice causes severe ataxia with Purkinje cell degeneration and cerebellar atrophy, partially resembling the consequences of haploinsufficiency of the human CAMTA1 locus. Gene-expression analysis identified a large collection of neuronal genes that were dysregulated in the brains of CAMTA1-mutant mice, and elucidation of a consensus sequence for binding of CAMTA proteins to DNA revealed the association of CAMTA-binding sites with many of these genes. We conclude that CAMTA1 plays an essential role in the control of Purkinje cell function and survival. CAMTA1-mutant mice provide a model to study the molecular mechanisms of neurodegenerative diseases and for screening potential therapeutic interventions for such disorders.
关键词：CAMTA2 ; dimerization ; palindromic DNA ; neural genes
