Khdc3-KO Mouse

Khdc3, also known as Filia, is a gene encoding a KH-domain protein. It is a component of the sub-cortical maternal complex (SCMC) which is essential for early embryogenesis and female fertility in mammals [3,4,5,6]. The SCMC is involved in processes such as zygote progression beyond the first embryonic cell divisions, and Khdc3 likely plays a role in maintaining genome stability during these early developmental stages [3,4,5,6].

In mouse models, acute deletion of TET enzymes led to decreased expression of Khdc3 in mouse embryonic stem cells (mESC), resulting in chromosome mis-segregation and aneuploidy. Restoring KHDC3 levels in triple Tet-deficient mESC prevented aneuploidy, indicating that TET proteins regulate Khdc3 gene expression, and TET deficiency causes mitotic infidelity and genome instability in mESC at least partly through decreased Khdc3 expression [1]. Also, female mice descended from ancestors with a Khdc3 mutation, despite being genetically wild-type themselves, had hepatic metabolic defects that persisted over multiple generations. The oocytes of Khdc3-null females and their wild-type descendants had dysregulation of multiple small RNAs, suggesting transgenerational inheritance of phenotypes related to Khdc3 ancestral mutation [2].

In conclusion, Khdc3 is crucial for early embryonic development and genome stability as demonstrated in mouse models. Its dysregulation can lead to aneuploidy in mESC and transgenerational metabolic defects. These findings from KO-related studies in mice provide insights into the role of Khdc3 in early development and potential implications for understanding certain genetic-related diseases and transgenerational phenotypes [1,2].

References:

1. Georges, Romain O, Sepulveda, Hugo, Angel, J Carlos, López-Moyado, Isaac F, Rao, Anjana. 2022. Acute deletion of TET enzymes results in aneuploidy in mouse embryonic stem cells through decreased expression of Khdc3. In Nature communications, 13, 6230. doi:10.1038/s41467-022-33742-7. https://pubmed.ncbi.nlm.nih.gov/36266342/

2. Senaldi, Liana, Hassan, Nora, Cullen, Sean, Conine, Colin, Smith-Raska, Matthew. 2024. Khdc3 Regulates Metabolism Across Generations in a DNA-Independent Manner. In bioRxiv : the preprint server for biology, , . doi:10.1101/2024.02.27.582278. https://pubmed.ncbi.nlm.nih.gov/38464133/

3. Bebbere, Daniela, Ariu, Federica, Bogliolo, Luisa, Falchi, Laura, Ledda, Sergio. 2014. Expression of maternally derived KHDC3, NLRP5, OOEP and TLE6 is associated with oocyte developmental competence in the ovine species. In BMC developmental biology, 14, 40. doi:10.1186/s12861-014-0040-y. https://pubmed.ncbi.nlm.nih.gov/25420964/

4. Qin, Dandan, Gao, Zheng, Xiao, Yi, Yi, Zhaohong, Li, Lei. 2019. The subcortical maternal complex protein Nlrp4f is involved in cytoplasmic lattice formation and organelle distribution. In Development (Cambridge, England), 146, . doi:10.1242/dev.183616. https://pubmed.ncbi.nlm.nih.gov/31575650/

5. Bebbere, D, Masala, L, Albertini, D F, Ledda, S. 2016. The subcortical maternal complex: multiple functions for one biological structure? In Journal of assisted reproduction and genetics, 33, 1431-1438. doi:. https://pubmed.ncbi.nlm.nih.gov/27525657/

6. Bebbere, D, Abazari-Kia, A, Nieddu, S, Albertini, D F, Ledda, S. 2020. Subcortical maternal complex (SCMC) expression during folliculogenesis is affected by oocyte donor age in sheep. In Journal of assisted reproduction and genetics, 37, 2259-2271. doi:10.1007/s10815-020-01871-x. https://pubmed.ncbi.nlm.nih.gov/32613414/