Dnase1l2-KO Mouse

Dnase1l2, or DNase1-like 2, is an endonuclease with metal-dependent endonuclease activity, having a broad pH range with an acidic optimum [2,5]. It plays a crucial role in DNA degradation processes, especially during the terminal differentiation of keratinocytes. This involves the removal of nuclear DNA in the formation of the stratum corneum, hair, nails, and in maintaining innate antimicrobial defense in the epidermis [3,4,8]. It may also be involved in biological processes related to the epithelial-mesenchymal transition [1]. Genetic models, such as knockout mice, have been essential in studying its functions.

In mouse models, inactivation of Dnase1l2 alone or in combination with other nucleases has provided insights into its role. For example, Dnase1l2 -/- mice showed aberrant retention of DNA in hair, nails, tongue, and esophagus epithelia, with the presence of nuclear DNA disturbing the normal arrangement of structural proteins in hair corneocytes and reducing hair's mechanical stress resistance [8]. In Dnase1l2 -/- Dnase2 Δep mice, nuclear DNA was retained in the stratum corneum, leading to parakeratosis, indicating cooperation between Dnase1l2 and Dnase2 in epidermal cornification [6]. Double deficiency of Trex2 and Dnase1l2 led to massive DNA fragment accumulation in the cornified layers of the tongue epithelium without activating inflammatory responses, suggesting their cooperation in lingual keratinocyte cornification [7].

In conclusion, Dnase1l2 is essential for DNA degradation during the terminal differentiation of keratinocytes in various tissues. Studies using gene knockout mouse models have revealed its role in maintaining the normal structure and function of skin appendages, epidermal cornification, and in preventing parakeratosis. Its potential as a carcinogenic marker in breast cancer, as well as its role in cystic fibrosis lung disease treatment and innate antimicrobial defense, highlights its significance in multiple disease areas [1,2,3].

References:

1. Liu, Chang-Rui, Meng, Fan-Hua. 2020. DNASE1L2, as a Carcinogenic Marker, Affects the Phenotype of Breast Cancer Cells Via Regulating Epithelial-Mesenchymal Transition Process. In Cancer biotherapy & radiopharmaceuticals, 36, 180-188. doi:10.1089/cbr.2019.3504. https://pubmed.ncbi.nlm.nih.gov/32343605/

2. Delfino, Danila, Mori, Giulia, Rivetti, Claudio, Pasut, Gianfranco, Percudani, Riccardo. 2021. Actin-Resistant DNase1L2 as a Potential Therapeutics for CF Lung Disease. In Biomolecules, 11, . doi:10.3390/biom11030410. https://pubmed.ncbi.nlm.nih.gov/33802146/

3. Eckhart, L, Fischer, H, Barken, K B, Tolker-Nielsen, T, Tschachler, E. 2007. DNase1L2 suppresses biofilm formation by Pseudomonas aeruginosa and Staphylococcus aureus. In The British journal of dermatology, 156, 1342-5. doi:. https://pubmed.ncbi.nlm.nih.gov/17459041/

4. Fischer, Heinz, Eckhart, Leopold, Mildner, Michael, Ghannadan, Minoo, Tschachler, Erwin. 2006. DNase1L2 degrades nuclear DNA during corneocyte formation. In The Journal of investigative dermatology, 127, 24-30. doi:. https://pubmed.ncbi.nlm.nih.gov/16902420/

5. Mori, Giulia, Delfino, Danila, Pibiri, Paola, Rivetti, Claudio, Percudani, Riccardo. 2022. Origin and significance of the human DNase repertoire. In Scientific reports, 12, 10364. doi:10.1038/s41598-022-14133-w. https://pubmed.ncbi.nlm.nih.gov/35725583/

6. Fischer, Heinz, Buchberger, Maria, Napirei, Markus, Tschachler, Erwin, Eckhart, Leopold. 2017. Inactivation of DNase1L2 and DNase2 in keratinocytes suppresses DNA degradation during epidermal cornification and results in constitutive parakeratosis. In Scientific reports, 7, 6433. doi:10.1038/s41598-017-06652-8. https://pubmed.ncbi.nlm.nih.gov/28743926/

7. Manils, Joan, Fischer, Heinz, Climent, Joan, Eckhart, Leopold, Soler, Concepció. 2017. Double deficiency of Trex2 and DNase1L2 nucleases leads to accumulation of DNA in lingual cornifying keratinocytes without activating inflammatory responses. In Scientific reports, 7, 11902. doi:10.1038/s41598-017-12308-4. https://pubmed.ncbi.nlm.nih.gov/28928425/

8. Fischer, Heinz, Szabo, Sandra, Scherz, Jennifer, Tschachler, Erwin, Eckhart, Leopold. 2011. Essential role of the keratinocyte-specific endonuclease DNase1L2 in the removal of nuclear DNA from hair and nails. In The Journal of investigative dermatology, 131, 1208-15. doi:10.1038/jid.2011.13. https://pubmed.ncbi.nlm.nih.gov/21307874/