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In this study, we used a conditional knockout mouse model to investigate the role of Smarca5, a member of the ISWI subfamily of such complexes, in early lymphocyte development. Smarca5 deficiency results in a developmental block at the DN3 stage of \u03b1\u03b2 thymocytes and pro-B stage of early B cells at which the rearrangement of Ag receptor loci occurs. It also disturbs the development of committed (CD73+) \u03b3\u03b4 thymocytes. The \u03b1\u03b2 thymocyte block is accompanied by massive apoptotic depletion of \u03b2-selected double-negative DN3 cells and premitotic arrest of CD4\/CD8 double-positive cells. Although Smarca5-deficient \u03b1\u03b2 T cell precursors that survived apoptosis were able to undergo a successful TCR\u03b2 rearrangement, they exhibited a highly abnormal mRNA profile, including the persistent expression of CD44 and CD25 markers characteristic of immature cells. We also observed that the p53 pathway became activated in these cells and that a deficiency of p53 partially rescued the defect in thymus cellularity (in contrast to early B cells) of Smarca5-deficient mice. However, the activation of p53 was not primarily responsible for the thymocyte developmental defects observed in the Smarca5 mutants. Our results indicate that Smarca5 plays a key role in the development of thymocytes undergoing \u03b2-selection, \u03b3\u03b4 thymocytes, and also B cell progenitors by regulating the transcription of early differentiation programs.<\/jats:p>","DOI":"10.4049\/jimmunol.1801684","type":"journal-article","created":{"date-parts":[[2019,5,8]],"date-time":"2019-05-08T19:15:22Z","timestamp":1557342922000},"page":"3434-3446","source":"Crossref","is-referenced-by-count":17,"title":["ISWI ATPase Smarca5 Regulates Differentiation of Thymocytes Undergoing \u03b2-Selection"],"prefix":"10.1093","volume":"202","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2452-3749","authenticated-orcid":false,"given":"Tomas","family":"Zikmund","sequence":"first","affiliation":[{"name":"BIOCEV, First Faculty of Medicine, Charles University , Vestec 25250 ,","place":["Czech Republic"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0267-4570","authenticated-orcid":false,"given":"Juraj","family":"Kokavec","sequence":"additional","affiliation":[{"name":"BIOCEV, First Faculty of Medicine, Charles University , Vestec 25250 ,","place":["Czech Republic"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5329-1812","authenticated-orcid":false,"given":"Tereza","family":"Turkova","sequence":"additional","affiliation":[{"name":"BIOCEV, First Faculty of Medicine, Charles University , Vestec 25250 ,","place":["Czech Republic"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Filipp","family":"Savvulidi","sequence":"additional","affiliation":[{"name":"Institute of Pathological Physiology, First Faculty of Medicine, Charles University , Prague 12853 ,","place":["Czech Republic"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6479-6592","authenticated-orcid":false,"given":"Helena","family":"Paszekova","sequence":"additional","affiliation":[{"name":"BIOCEV, First Faculty of Medicine, Charles University , Vestec 25250 ,","place":["Czech Republic"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0315-5668","authenticated-orcid":false,"given":"Sona","family":"Vodenkova","sequence":"additional","affiliation":[{"name":"Institute of Experimental Medicine, Czech Academy of Sciences , Prague 14220 ,","place":["Czech Republic"]},{"name":"Third Faculty of Medicine, Charles University , Prague 10000 ,","place":["Czech Republic"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Radislav","family":"Sedlacek","sequence":"additional","affiliation":[{"name":"Czech Centre for Phenogenomics, Institute of Molecular Genetics, Czech Academy of Sciences , Vestec 25250 ,","place":["Czech Republic"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arthur I","family":"Skoultchi","sequence":"additional","affiliation":[{"name":"Department of Cell Biology, Albert Einstein College of Medicine , Bronx 10461, NY"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7236-6894","authenticated-orcid":false,"given":"Tomas","family":"Stopka","sequence":"additional","affiliation":[{"name":"BIOCEV, First Faculty of Medicine, Charles University , Vestec 25250 ,","place":["Czech Republic"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2019,6,15]]},"reference":[{"key":"2025030417562611300_r1","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1038\/nri2232","article-title":"Launching the T-cell-lineage developmental programme","volume":"8","author":"Rothenberg","year":"2008","journal-title":"Nat. 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