Ataxia and Purkinje cell degeneration in mice lacking the CAMTA1 transcription factor

Abstract

Significance Neurodegenerative 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.

Integrator of Stress Responses Calmodulin Binding Transcription Activator 1 (Camta1) Regulates miR-212/miR-132 Expression and Insulin Secretion

“…It is critically involved in establishing mature functional alpha, beta, and PP cells in islets (18), in the maintenance of mature beta cell identity and function (20,21), and in beta-to-alpha cell reprogramming (22). Additionally, the influence of CAMTAs on neuronal survival has been suggested to be subject to signal-dependent regulation by the MEF2/HDAC5/CaMKII pathway (23), which has recently been targeted as a novel treatment for both type 1 and type 2 diabetes (24).…”

Association of a Locus in theCAMTA1Gene With Survival in Patients With Sporadic Amyotrophic Lateral Sclerosis

“…29 Mutant CAMTA1 knockout mice, disrupted in the CG-1 domain, show severe ataxia and neuronal atrophy approximating the phenotype of haploinsufficiency observed in patients with NPCA. 30 Furthermore, the identification of the consensus sequences of the DNA-binding site of the CG-1 domain combined with expression analyses in CAMTA1 knockout mice have shown more than 80 neural-related genes regulated by CAMTA1 . 30 The finding of a gene involved in cerebellar disease in ALS is not surprising given that trinucleotide repeat expansion in the ataxin 2 ( ATXN2 ) gene causes spinocerebellar ataxia or ALS, 31 the finding of C9orf72 pathologic mechanisms in the cerebellum of patients with ALS, 32 and the discovery of abnormal eye gaze in patients with ALS.…”

“…30 Furthermore, the identification of the consensus sequences of the DNA-binding site of the CG-1 domain combined with expression analyses in CAMTA1 knockout mice have shown more than 80 neural-related genes regulated by CAMTA1 . 30 The finding of a gene involved in cerebellar disease in ALS is not surprising given that trinucleotide repeat expansion in the ataxin 2 ( ATXN2 ) gene causes spinocerebellar ataxia or ALS, 31 the finding of C9orf72 pathologic mechanisms in the cerebellum of patients with ALS, 32 and the discovery of abnormal eye gaze in patients with ALS. 33,34 Increasing evidence suggests an association between ALS and cerebellar degeneration that is currently underrecognized, in the same way as the association between ALS and frontotemporal dementia remained undetected until recently.…”

The calmodulin-binding transcription activator CAMTA1 is required for long-term memory formation in mice

“…A role for CAMTA1 for the structural integrity of neurons has recently been shown for Purkinje cells in the cerebellum (Long et al 2014). Mice lacking the Camta1 gene suffer from progressive postnatal neuronal atrophy in the cerebellum leading to motor deficits and ataxia (Long et al 2014).…”

“…A role for CAMTA1 for the structural integrity of neurons has recently been shown for Purkinje cells in the cerebellum (Long et al 2014). Mice lacking the Camta1 gene suffer from progressive postnatal neuronal atrophy in the cerebellum leading to motor deficits and ataxia (Long et al 2014). Furthermore, ectopic expression of CAMTA1 in a neuroblastoma cell line led to the formation of neurite-like processes in these cells (Henrich et al 2011).…”