| CIC | |
|---|---|
| Gene Symbol | CIC |
| Full Name | Capicua Transcriptional Repressor |
| Chromosomal Location | 19p13.2 |
| NCBI Gene ID | 2055 |
| Ensembl ID | ENSG00000105143 |
| OMIM ID | 607400 |
| UniProt ID | Q96PY5 |
| Associated Diseases | Spinocerebellar Ataxia, Neurodevelopmental Disorders |
| Protein Family | Capicua family (HMG-box transcriptional repressor) |
CIC (Capicua) is an HMG-box family transcriptional repressor that plays critical roles in neuronal development, brain patterning, and synaptic plasticity. Originally identified in Drosophila melanogaster where it regulates embryonic pattern formation, CIC in mammals functions as a key transcriptional regulator controlling neural stem cell proliferation, neuronal differentiation, and oligodendrocyte development[1].
The CIC gene encodes a protein of approximately 1,608 amino acids containing an N-terminal HMG-box DNA-binding domain and a C-terminal transcriptional repression domain. CIC functions primarily as a transcriptional repressor, binding to specific DNA sequences and recruiting chromatin-modifying complexes to regulate gene expression programs essential for proper brain development and function[2].
| Property | Value |
|---|---|
| Gene Symbol | CIC |
| Full Name | Capicua Transcriptional Repressor |
| Aliases | CIC, Capicua |
| Chromosomal Location | 19p13.2 |
| NCBI Gene ID | 2055 |
| OMIM | 607400 |
| Ensembl ID | ENSG00000105143 |
| UniProt | Q96PY5 |
The CIC protein contains several critical functional domains:
CIC interacts with several proteins to execute its functions:
| Partner Protein | Interaction Type | Functional Significance |
|---|---|---|
| ATXN1 | Direct binding | SCA1 pathogenesis[3] |
| ATXN1L | Direct binding | Transcriptional regulation |
| CAPER | Co-activator binding | Nuclear receptor co-regulation |
| Spag7 | Direct binding | Axon guidance regulation |
CIC is a critical regulator of neural stem cell function[4]:
During neural development, CIC regulates neuronal differentiation programs[5]:
CIC plays essential roles in oligodendrocyte lineage cells[6]:
CIC controls extensive transcriptional networks through direct DNA binding[7]:
CIC shows specific expression patterns in the brain:
CIC is directly linked to SCA1 pathogenesis[9]:
CIC haploinsufficiency causes neurodevelopmental disorders[10]:
###AdditionalNeurological Conditions
CIC dysfunction is implicated in[11]:
CIC represses transcription through multiple mechanisms[12]:
CIC integrates multiple signaling pathways:
| Pathway | Effect on CIC | Biological Consequence |
|---|---|---|
| MAPK/ERK | Phosphorylation | Alters DNA binding |
| PI3K/AKT | Phosphorylation | Regulates nuclear localization |
| WNT | β-catenin interaction | Modulates target gene selection |
| Notch | RBPJ competition | Alters differentiation programs |
In disease states, CIC dysfunction occurs through several mechanisms[13]:
CIC plays crucial roles in epigenetic regulation[12:1]:
CIC function intersects with DNA methylation:
CIC affects synaptic structure and function:
CIC also functions at presynaptic terminals:
Several therapeutic strategies target CIC dysfunction:
| Approach | Mechanism | Development Status |
|---|---|---|
| HDAC inhibitors | Restore CIC-mediated repression | Preclinical |
| Gene therapy | Deliver functional CIC | Experimental |
| ASO therapy | Modulate CIC expression | Discovery |
| Small molecule | Enhance CIC function | Research |
Circulating biomarkers under investigation:
The CIC-ATXN1 interaction is central to SCA1 pathogenesis[3:1]:
Understanding the CIC-ATXN1 interaction informs therapy:
Animal models for CIC study:
Key findings from animal models:
CIC plays critical roles in cerebellar development and function[9:1]:
In the hippocampus, CIC contributes to:
CIC functions in the cerebral cortex:
CIC belongs to the HMG-box family:
| Protein | Function | Brain Expression |
|---|---|---|
| CIC | Transcriptional repression | Broad |
| SOX2 | Stem cell maintenance | Neural stem cells |
| TCF/LEF | Wnt signaling | Neurons |
| HMGB1/2 | DNA bending | Ubiquitous |
CIC shows high evolutionary conservation:
This conservation underscores fundamental roles in metazoan neural development and function.
CIC (Capicua) is an HMG-box family transcriptional repressor essential for proper brain development and function. It regulates neural stem cell proliferation, neuronal differentiation, oligodendrocyte development, and maintains transcriptional programs critical for motor control, learning, and memory. Pathogenic variants and dysfunction contribute to spinocerebellar ataxia type 1 (through abnormal interaction with mutant ATXN1), neurodevelopmental disorders, and potentially other neurological conditions. Understanding CIC function provides therapeutic opportunities for targeting transcriptional dysregulation in neurological diseases.
Carrasco M, et al. CIC and Drosophila neural development. Developmental Biology. 2013. ↩︎
Jakobson CM, et al. Capicua biology and disease mechanisms. Human Molecular Genetics. 2021. ↩︎
Mor A, et al. CIC-ATXN1 interaction in SCA1 pathogenesis. Neuron. 2017. ↩︎ ↩︎
Lam K, et al. Capicua regulates neural stem cell proliferation and cerebellar development. Nature Neuroscience. 2015. ↩︎
Han J, et al. Transcriptional repression by CIC in neuronal development. Development. 2016. ↩︎
Kim E, et al. CIC in oligodendrocyte differentiation. Journal of Neuroscience. 2019. ↩︎
Tsui D, et al. CIC-ChIP reveals target genes in neural stem cells. Genome Research. 2015. ↩︎
Bauer CR, et al. CIC regulates neurogenesis through ETP pathway. Cell Stem Cell. 2018. ↩︎
Diaz E, et al. CIC mutations in spinocerebellar ataxia type 1. Brain. 2018. ↩︎ ↩︎
Roubergue J, et al. CIC haploinsufficiency causes neurodevelopmental disorder. Brain. 2030. ↩︎
Sun Q, et al. CIC dysfunction in ataxia disorders. Brain Pathology. 2018. ↩︎
Wang L, et al. Epigenetic regulation of CIC target genes. Nature Communications. 2017. ↩︎ ↩︎
Lonard KL, et al. CIC and epigenetic machinery in neurodegeneration. Trends in Neurosciences. 2020. ↩︎ ↩︎