Foxi2, a member of the Foxi class of Forkhead transcription factors, plays crucial roles in multiple biological processes. It is involved in ectodermal germ layer specification, acting as a master regulator along with Sox3 in Xenopus [3]. It also serves as a maternal activator of the zygotic ectoderm activator Foxi1e in Xenopus [4]. In addition, Foxi2 in the hypothalamus controls systemic energy metabolism by regulating the expression of the neuropeptide AgRP, with its overexpression leading to increased food intake, reduced energy expenditure, obesity, and insulin resistance, while global Foxi2 -mutant mice are leaner and resistant to diet-induced obesity [5].

In a 10-year-old Iraqi girl with overlapping features of CFC, NS, Costello syndromes, and ectodermal dysplasia, a de novo deletion in the FOXI2 gene was identified, and FOXI2 was found to be expressed in the basal cell layer of the skin, overlapping with P63, suggesting it may contribute to ectodermal dysplasia [1]. In clear cell renal cell carcinoma (ccRCC), FOXI2 is downregulated and hypermethylated, and its expression is correlated with prognosis. Overexpression of FOXI2 can induce cell cycle arrest and inhibit cell proliferation in vitro [2]. In oral cancer and pancreatic ductal adenocarcinoma, methylation of FOXI2 is associated with cancer development and prognosis [6,7].

In conclusion, Foxi2 is essential for ectodermal development and energy metabolism regulation. Studies on Foxi2, including those using potential genetic models like KO or CKO mouse models (not directly detailed in the provided references but inferred from general gene-function research approaches), contribute to understanding its role in ectodermal-related disorders, cancers such as ccRCC, oral cancer, and pancreatic ductal adenocarcinoma.

References:

1. Kurban, Mazen, Zeineddine, Savo Bou, Hamie, Lamiaa, Bitar, Fadi, Nemer, Georges. . FOXI2: a possible gene contributing to ectodermal dysplasia. In European journal of dermatology : EJD, 27, 641-645. doi:10.1684/ejd.2017.3130. https://pubmed.ncbi.nlm.nih.gov/29165300/

2. Zhou, Shuai, Cheng, Cong, Liao, Yi Xiang, Zhang, Xiu Qin, Yang, Tao. 2024. Epigenetic regulation of FOXI2 promotes clear cell renal cell carcinoma progression. In Heliyon, 10, e29218. doi:10.1016/j.heliyon.2024.e29218. https://pubmed.ncbi.nlm.nih.gov/38628758/

3. Hendrickson, Clark L, Blitz, Ira L, Hussein, Amina, Kofron, Matthew J, Cho, Ken W Y. 2025. Foxi2 and Sox3 are master regulators controlling ectoderm germ layer specification. In bioRxiv : the preprint server for biology, , . doi:10.1101/2025.01.09.632114. https://pubmed.ncbi.nlm.nih.gov/39829826/

4. Cha, Sang-Wook, McAdams, Meredith, Kormish, Jay, Wylie, Christopher, Kofron, Matthew. 2012. Foxi2 is an animally localized maternal mRNA in Xenopus, and an activator of the zygotic ectoderm activator Foxi1e. In PloS one, 7, e41782. doi:10.1371/journal.pone.0041782. https://pubmed.ncbi.nlm.nih.gov/22848601/

5. Fan, Yatong, Sheng, Sufang, Guo, Cunle, Liao, Yunfei, Chang, Yongsheng. . Forkhead Box i2 Transcription Factor Regulates Systemic Energy Metabolism Via Neuropeptide AgRP. In Diabetes, 71, 2106-2122. doi:10.2337/db22-0002. https://pubmed.ncbi.nlm.nih.gov/35856496/

6. Foy, Jean-Philippe, Pickering, Curtis R, Papadimitrakopoulou, Vassiliki A, Mao, Li, Saintigny, Pierre. 2015. New DNA methylation markers and global DNA hypomethylation are associated with oral cancer development. In Cancer prevention research (Philadelphia, Pa.), 8, 1027-35. doi:10.1158/1940-6207.CAPR-14-0179. https://pubmed.ncbi.nlm.nih.gov/26342026/

7. Zhang, Zihan, Zhu, Rui, Sun, Wentian, Wang, Jun, Liu, Jin. 2021. Analysis of Methylation-driven Genes in Pancreatic Ductal Adenocarcinoma for Predicting Prognosis. In Journal of Cancer, 12, 6507-6518. doi:10.7150/jca.53208. https://pubmed.ncbi.nlm.nih.gov/34659542/