Id4, also known as Inhibitor of DNA binding/differentiation 4, is a transcriptional regulator that belongs to the inhibitor of differentiation (ID) protein family. It plays crucial roles in various biological processes by interacting with other transcription factors to inhibit their activity, influencing cell differentiation, survival, growth, and metastasis [4]. It is involved in multiple key pathways, such as those related to development and cancer-associated processes [1,5]. Genetic models, especially knockout (KO) mouse models, have been instrumental in understanding its functions.

In Id4-deficient mice, the submandibular glands were smaller and showed accelerated differentiation, along with dry mouth symptoms and Th17 expansion in splenocytes, suggesting its role in salivary gland homeostasis [2]. In the context of ependymal cell development, Id4-deficient mice displayed altered ventricular cell cytoarchitecture, decreased ependymal cell number, and enlarged ventricles, indicating its requirement for normal ependymal cell development [3]. In the adult hippocampal dentate gyrus, deletion of Id4 activated neural stem cell (NSC) proliferation without evoking neuron generation, showing that Id4 maintains NSC quiescence [6].

In conclusion, Id4 is essential for maintaining the balance in processes like cell differentiation, homeostasis, and stem cell quiescence. Studies using KO mouse models have revealed its significance in diseases related to salivary gland function, ependymal cell development, and neural stem cell regulation, providing valuable insights into potential disease mechanisms and therapeutic targets.

References:

1. Baker, Laura A, Holliday, Holly, Swarbrick, Alexander. 2016. ID4 controls luminal lineage commitment in normal mammary epithelium and inhibits BRCA1 function in basal-like breast cancer. In Endocrine-related cancer, 23, R381-92. doi:10.1530/ERC-16-0196. https://pubmed.ncbi.nlm.nih.gov/27412917/

2. Hayashi, Yoshikazu, Kimura, Soi, Yano, Ena, Jimi, Eijiro, Kawakubo-Yasukochi, Tomoyo. 2022. Id4 modulates salivary gland homeostasis and its expression is downregulated in IgG4-related disease via miR-486-5p. In Biochimica et biophysica acta. Molecular cell research, 1870, 119404. doi:10.1016/j.bbamcr.2022.119404. https://pubmed.ncbi.nlm.nih.gov/36535369/

3. Rocamonde, Brenda, Herranz-Pérez, Vicente, Garcia-Verdugo, Jose Manuel, Huillard, Emmanuelle. 2021. ID4 Is Required for Normal Ependymal Cell Development. In Frontiers in neuroscience, 15, 668243. doi:10.3389/fnins.2021.668243. https://pubmed.ncbi.nlm.nih.gov/33967685/

4. Choi, Jin-Ho, Park, Joo Dong, Choi, Seung Hee, Jang, Hye Jung, Park, Kyung-Soon. 2023. ELK3-ID4 axis governs the metastatic features of triple negative breast cancer. In Oncology research, 32, 127-138. doi:10.32604/or.2023.042945. https://pubmed.ncbi.nlm.nih.gov/38188675/

5. Patel, Divya, Morton, Derrick J, Carey, Jason, Havrda, Mathew C, Chaudhary, Jaideep. 2014. Inhibitor of differentiation 4 (ID4): From development to cancer. In Biochimica et biophysica acta, 1855, 92-103. doi:10.1016/j.bbcan.2014.12.002. https://pubmed.ncbi.nlm.nih.gov/25512197/

6. Zhang, Runrui, Boareto, Marcelo, Engler, Anna, Iber, Dagmar, Taylor, Verdon. . Id4 Downstream of Notch2 Maintains Neural Stem Cell Quiescence in the Adult Hippocampus. In Cell reports, 28, 1485-1498.e6. doi:10.1016/j.celrep.2019.07.014. https://pubmed.ncbi.nlm.nih.gov/31390563/