Fgd2, a member of the FGD family, encodes a Rho guanine nucleotide exchange factor. It contains a Dbl homology (DH) domain responsible for guanine nucleotide exchange of CDC42, activating downstream factors, and two pleckstrin homology domains segregated by a FYVE domain [1,4]. By specifically activating Cdc42, Fgd2 controls cytoskeleton-dependent membrane rearrangements and is involved in leukocyte signaling and vesicle trafficking in antigen-presenting cells [2]. It also plays a role in embryonic development as its transcripts are present in diverse tissues during mouse embryogenesis [4].

A loss-of-function allele of Fgd2 generated by gene targeting reduced the transmission ratio of the t haplotype t(h49), directly demonstrating its role as a Distorter in transmission ratio distortion (TRD) in mice. This shows that Fgd2 identifies a second Rho G protein signaling pathway promoting TRD [3].

In conclusion, Fgd2 is crucial for regulating cytoskeleton-related processes, embryonic development, and sperm-related inheritance mechanisms like TRD. The gene knockout mouse model has been valuable in revealing its role in TRD, providing insights into the genetic mechanisms underlying this reproductive phenomenon.

References:

1. Chuan, Junlan, He, Shiyu, Xie, Tian, Wang, Ganggang, Yang, Zhenglin. 2020. Characterization of guanine nucleotide exchange activity of DH domain of human FGD2. In Protein expression and purification, 176, 105693. doi:10.1016/j.pep.2020.105693. https://pubmed.ncbi.nlm.nih.gov/32681954/

2. Huber, Christoph, Mårtensson, Annica, Bokoch, Gary M, Nemazee, David, Gavin, Amanda L. 2008. FGD2, a CDC42-specific exchange factor expressed by antigen-presenting cells, localizes to early endosomes and active membrane ruffles. In The Journal of biological chemistry, 283, 34002-12. doi:10.1074/jbc.M803957200. https://pubmed.ncbi.nlm.nih.gov/18838382/

3. Bauer, Hermann, Véron, Nathalie, Willert, Jürgen, Herrmann, Bernhard G. . The t-complex-encoded guanine nucleotide exchange factor Fgd2 reveals that two opposing signaling pathways promote transmission ratio distortion in the mouse. In Genes & development, 21, 143-7. doi:. https://pubmed.ncbi.nlm.nih.gov/17234881/

4. Pasteris, N G, Gorski, J L. . Isolation, characterization, and mapping of the mouse and human Fgd2 genes, faciogenital dysplasia (FGD1; Aarskog syndrome) gene homologues. In Genomics, 60, 57-66. doi:. https://pubmed.ncbi.nlm.nih.gov/10458911/