Exd1, or Exonuclease 3'-5' domain-containing protein 1, is involved in the PIWI-interacting RNA (piRNA) biogenesis pathway, which is crucial for restricting transposon activity in animal gonads to ensure fertility [1,2,3].

In mouse models, loss-of-function experiments have provided insights into Exd1's role. In Exd1 mutant mice, MILI-triggered piRNA biogenesis is greatly reduced. 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]. Also, loss of Exd1 reduces sequences generated by MILI slicing, impacts biogenesis of MIWI2 piRNAs, and de-represses LINE1 retrotransposons, suggesting that EXD1, as an RNA adaptor within a PET (PIWI-EXD1-Tdrd12) complex, is involved in coordinating piRNA-mediated transposon silencing in the nucleus and cytoplasm [3].

In conclusion, Exd1 is essential for piRNA biogenesis in mouse male germ cells. Studies using Exd1 KO mouse models have revealed its role in maintaining the integrity of the germline genome by regulating piRNA levels and controlling transposon activity, which is relevant to understanding male fertility and germ cell-related diseases [1,2,3].

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/