Csmd1, short for CUB and Sushi Multiple Domains 1, is a tumour suppressor gene encoding a large membrane-bound protein with a single transmembrane domain and a potential tyrosine phosphorylation site. It is involved in multiple biological processes such as development, complement control, neurodevelopment, and cancer progression [3]. The complement pathway, in which Csmd1 may play a regulatory role, is important for innate immune response and has emergent functions in modulating neural development and synaptic activity [2]. Genetic models, like knockout mice, are valuable for studying Csmd1's functions.

In knockout mouse models, Csmd1-deficient mice showed increased levels of complement component C3, more colocalization of C3 with presynaptic terminals, fewer retinogeniculate synapses, and abnormal segregation of eye-specific retinal inputs in the visual thalamus during the critical period of circuit refinement. Also, loss of Csmd1 enhanced synaptosome engulfment by microglia in vitro, depending on microglial complement receptor CR3 activity. These suggest Csmd1 regulates complement-mediated synapse elimination in the brain during development [1]. In mammary gland development, Csmd1 knockout mice had increased ductal development during early puberty, indicating a role in regulating mammary gland development [4]. In gliomas, downregulation of Csmd1 in a PDGFB-induced brain tumor mouse model led to reduced survival, and ectopic expression of Csmd1 in glioma cell lines decreased their aggressiveness, showing its role as a tumor suppressor in gliomas [5].

In conclusion, Csmd1 plays essential roles in brain development by regulating complement-mediated synapse elimination and in mammary gland development. In diseases, it acts as a tumor suppressor in gliomas. The study of Csmd1 using gene knockout mouse models has provided valuable insights into its functions in these biological processes and disease conditions.

References:

1. Baum, Matthew L, Wilton, Daniel K, Fox, Rachel G, Johnson, Matthew B, Stevens, Beth. 2024. CSMD1 regulates brain complement activity and circuit development. In Brain, behavior, and immunity, 119, 317-332. doi:10.1016/j.bbi.2024.03.041. https://pubmed.ncbi.nlm.nih.gov/38552925/

2. Werren, Elizabeth A, Peirent, Emily R, Jantti, Henna, Srivastava, Anshika, Bielas, Stephanie L. 2024. Biallelic variants in CSMD1 are implicated in a neurodevelopmental disorder with intellectual disability and variable cortical malformations. In Cell death & disease, 15, 379. doi:10.1038/s41419-024-06768-6. https://pubmed.ncbi.nlm.nih.gov/38816421/

3. Ermis Akyuz, Esra, Bell, Sandra M. 2022. The Diverse Role of CUB and Sushi Multiple Domains 1 (CSMD1) in Human Diseases. In Genes, 13, . doi:10.3390/genes13122332. https://pubmed.ncbi.nlm.nih.gov/36553598/

4. Burgess, Samuel J, Gibbs, Hannah, Toomes, Carmel, Coletta, Patricia L, Bell, Sandra M. 2021. The Role of Csmd1 during Mammary Gland Development. In Genes, 12, . doi:10.3390/genes12020162. https://pubmed.ncbi.nlm.nih.gov/33530646/

5. Tuysuz, Emre Can, Mourati, Eleni, Rosberg, Rebecca, Pietras, Alexander, Blom, Anna M. 2024. Tumor suppressor role of the complement inhibitor CSMD1 and its role in TNF-induced neuroinflammation in gliomas. In Journal of experimental & clinical cancer research : CR, 43, 98. doi:10.1186/s13046-024-03019-6. https://pubmed.ncbi.nlm.nih.gov/38561856/