Exd1, short for Exonuclease domain-containing 1, is involved in the biogenesis of PIWI-interacting RNAs (piRNAs) in animal gonads, a process crucial for restricting transposon activity to ensure fertility [2,3]. It functions within the context of the piRNA pathway, which is integral to RNA regulation in germ cells. Genetic models, especially mouse models, have been valuable in studying Exd1's function.

In mouse studies, Exd1 was found to localize to the intermitochondrial cement (IMC) in meiotic spermatocytes, along with EXD2, and is suggested to function in IMC-mediated RNA regulation in postnatal male germ cells [1]. Using artificial piRNA precursors, researchers demonstrated that MILI-triggered piRNA biogenesis is greatly reduced in the Exd1 mutant. In the sensitized Exd1 mutant (Exd1-/-;Tdrd12+/-), diminished MIWI2 piRNA levels de-repress LINE1 retrotransposons, leading to infertility, indicating that EXD1 enhances MIWI2 piRNA biogenesis via interaction with TDRD12 [2]. Loss of Exd1 also impacts the biogenesis of MIWI2 piRNAs, reduces sequences generated by MILI slicing, and de-represses LINE1 retrotransposons [3].

In conclusion, Exd1 is essential for the proper biogenesis of MIWI2 piRNAs, which is vital for suppressing transposons in mouse germ cells. The study of Exd1 knockout mouse models has revealed its critical role in maintaining genomic stability in the germline, providing insights into the mechanisms underlying male infertility related to disruptions in the piRNA pathway.

References:

1. Olotu, Opeyemi, Dowling, Mark, Homolka, David, Pillai, Ramesh S, Kotaja, Noora. 2023. Intermitochondrial cement (IMC) harbors piRNA biogenesis machinery and exonuclease domain-containing proteins EXD1 and EXD2 in mouse spermatocytes. In Andrology, 11, 710-723. doi:10.1111/andr.13361. https://pubmed.ncbi.nlm.nih.gov/36624638/

2. Pandey, Radha Raman, Homolka, David, Olotu, Opeyemi, Kotaja, Noora, Pillai, Ramesh S. . Exonuclease Domain-Containing 1 Enhances MIWI2 piRNA Biogenesis via Its Interaction with TDRD12. In Cell reports, 24, 3423-3432.e4. doi:10.1016/j.celrep.2018.08.087. https://pubmed.ncbi.nlm.nih.gov/30257204/

3. Yang, Zhaolin, Chen, Kuan-Ming, Pandey, Radha Raman, McCarthy, Andrew A, Pillai, Ramesh S. 2015. PIWI Slicing and EXD1 Drive Biogenesis of Nuclear piRNAs from Cytosolic Targets of the Mouse piRNA Pathway. In Molecular cell, 61, 138-52. doi:10.1016/j.molcel.2015.11.009. https://pubmed.ncbi.nlm.nih.gov/26669262/