Arl2, an ADP ribosylation factor-like GTPase, is crucial for regulating multiple cellular processes. It is highly conserved, ubiquitously expressed, and belongs to the Arf subfamily of the Ras superfamily. Arl2 plays fundamental roles in controlling mitochondrial fusion, microtubule assembly, and trafficking of lipid-modified proteins between different compartments [2,4]. It also has implications in various biological processes like neural stem cell division, cortical development, oocyte meiosis, and homologous recombination repair [1,3,5]. Genetic models, such as KO/CKO mouse models, have been invaluable in studying these functions.

In mouse models, Arl2 knockdown in neural progenitor cells (NPCs) impairs NPC proliferation and neuronal migration, with diminished centrosomal microtubule growth and delocalization of centrosomal proteins. Overexpression of Cdk5rap2 can rescue the neurogenesis defects caused by Arl2 KD, indicating Arl2's role in mouse cortical development via microtubule growth through Cdk5rap2 [1]. In colon cancer stem cells, depletion of ARL2 leads to M phase arrest in non-CSC cells and DNA break stress-induced apoptosis in CSCs. ARL2 is also required for homologous recombination repair [3]. Conditional deletion of ARL2 in mouse retina during embryonic development leads to distorted nuclear layers, disrupted microtubule cytoskeleton, and failure of outer segment formation [6].

In conclusion, Arl2 is essential for multiple biological functions including microtubule-related processes, mitochondrial fusion, and cellular repair mechanisms. Mouse KO/CKO models have revealed its significance in cortical development and colon cancer stem cell survival. These studies contribute to understanding the underlying mechanisms of related diseases, potentially providing new therapeutic targets.

References:

1. Ma, Dongliang, Lin, Kun-Yang, Suresh, Divya, Chen, Teng, Wang, Hongyan. 2024. Arl2 GTPase associates with the centrosomal protein Cdk5rap2 to regulate cortical development via microtubule organization. In PLoS biology, 22, e3002751. doi:10.1371/journal.pbio.3002751. https://pubmed.ncbi.nlm.nih.gov/39137170/

2. Fansa, Eyad K, Wittinghofer, Alfred. 2016. Sorting of lipidated cargo by the Arl2/Arl3 system. In Small GTPases, 7, 222-230. doi:. https://pubmed.ncbi.nlm.nih.gov/27806215/

3. Lee, Hani, Choi, SeokGyeong, Ha, Sojung, Yoon, Sukjoon, Kim, Woo-Young. 2022. ARL2 is required for homologous recombination repair and colon cancer stem cell survival. In FEBS open bio, 12, 1523-1533. doi:10.1002/2211-5463.13438. https://pubmed.ncbi.nlm.nih.gov/35567502/

4. Francis, Joshua W, Turn, Rachel E, Newman, Laura E, Schiavon, Cara, Kahn, Richard A. 2016. Higher order signaling: ARL2 as regulator of both mitochondrial fusion and microtubule dynamics allows integration of 2 essential cell functions. In Small GTPases, 7, 188-196. doi:. https://pubmed.ncbi.nlm.nih.gov/27400436/

5. Zhou, Chun-Xiang, Wang, Yang, Shi, Li-Ya, Zhang, Dong, Xia, Zheng-Rong. 2020. GTPases Arf5 and Arl2 function partially distinctly during oocyte meiosis. In Journal of cellular biochemistry, 122, 198-208. doi:10.1002/jcb.29839. https://pubmed.ncbi.nlm.nih.gov/32985032/

6. Gerstner, Cecilia D, Reed, Michelle, Dahl, Tiffanie M, Frederick, Jeanne M, Baehr, Wolfgang. 2022. Arf-like Protein 2 (ARL2) Controls Microtubule Neogenesis during Early Postnatal Photoreceptor Development. In Cells, 12, . doi:10.3390/cells12010147. https://pubmed.ncbi.nlm.nih.gov/36611941/