Srrm3, or serine/arginine repetitive matrix protein 3, is an RNA binding protein that plays a crucial role in alternative splicing, especially of microexons. It is involved in regulating gene expression relevant to various biological processes such as vesicle transport, exocytosis, and the function of the nervous system. Genetic models, like gene knockout (KO) mouse models, have been instrumental in studying its functions [1,3,4,5].

In pancreatic islets, Srrm3 regulates a conserved program of alternative microexons (IsletMICs). Depletion of Srrm3 in human and rat beta cell lines, mouse islets, or repression of IsletMICs leads to inappropriate insulin secretion. Mice with Srrm3 mutations show defects in islet cell identity and function, resulting in hyperinsulinaemic hypoglycaemia [1]. In photoreceptors, deletion of Srrm3 in zebrafish causes widespread down-regulation of microexon inclusion, transcriptomic alterations, severe photoreceptor defects, and blindness, indicating its importance in maintaining outer segment integrity and vision [3]. In the context of castration-resistant neuroendocrine prostate cancer, SRRM3 is expressed in certain phenotypes and induces alternative splicing of REST to REST4, exacerbating the expression of REST-repressed genes [2]. In addition, in the ear, SRRM3 can regulate many of the same exons as SRRM4, and in cortical neurons, overlapping SRRM3-SRRM4 activity regulates the development of interneuronal inhibition. Mice with mutations in both Srrm3 and Srrm4 die neonatally and exhibit severe splicing defects [4,5].

In conclusion, Srrm3 is essential for multiple biological processes. Model-based research, particularly KO mouse models, has revealed its role in diseases such as diabetes, retinal diseases, and prostate cancer. Understanding Srrm3 function provides insights into the molecular mechanisms underlying these diseases, potentially paving the way for new therapeutic strategies.

References:

1. Juan-Mateu, Jonàs, Bajew, Simon, Miret-Cuesta, Marta, Valcárcel, Juan, Irimia, Manuel. 2023. Pancreatic microexons regulate islet function and glucose homeostasis. In Nature metabolism, 5, 219-236. doi:10.1038/s42255-022-00734-2. https://pubmed.ncbi.nlm.nih.gov/36759540/

2. Labrecque, Mark P, Brown, Lisha G, Coleman, Ilsa M, Nelson, Peter S, Morrissey, Colm. 2021. RNA Splicing Factors SRRM3 and SRRM4 Distinguish Molecular Phenotypes of Castration-Resistant Neuroendocrine Prostate Cancer. In Cancer research, 81, 4736-4750. doi:10.1158/0008-5472.CAN-21-0307. https://pubmed.ncbi.nlm.nih.gov/34312180/

3. Ciampi, Ludovica, Mantica, Federica, López-Blanch, Laura, Head, Sarah A, Irimia, Manuel. 2022. Specialization of the photoreceptor transcriptome by Srrm3-dependent microexons is required for outer segment maintenance and vision. In Proceedings of the National Academy of Sciences of the United States of America, 119, e2117090119. doi:10.1073/pnas.2117090119. https://pubmed.ncbi.nlm.nih.gov/35858306/

4. Nakano, Yoko, Wiechert, Susan, Fritzsch, Bernd, Bánfi, Botond. 2020. Inhibition of a transcriptional repressor rescues hearing in a splicing factor-deficient mouse. In Life science alliance, 3, . doi:10.26508/lsa.202000841. https://pubmed.ncbi.nlm.nih.gov/33087486/

5. Nakano, Yoko, Wiechert, Susan, Bánfi, Botond. . Overlapping Activities of Two Neuronal Splicing Factors Switch the GABA Effect from Excitatory to Inhibitory by Regulating REST. In Cell reports, 27, 860-871.e8. doi:10.1016/j.celrep.2019.03.072. https://pubmed.ncbi.nlm.nih.gov/30995482/