{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,7]],"date-time":"2025-11-07T09:43:46Z","timestamp":1762508626717,"version":"3.40.5"},"reference-count":48,"publisher":"Public Library of Science (PLoS)","issue":"10","license":[{"start":{"date-parts":[[2021,10,28]],"date-time":"2021-10-28T00:00:00Z","timestamp":1635379200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"NIH","award":["NIHRO1DK096137"],"award-info":[{"award-number":["NIHRO1DK096137"]}]},{"name":"NIH","award":["P20GM11312"],"award-info":[{"award-number":["P20GM11312"]}]},{"name":"DaCCoTA CTR NIH","award":["U54GM128729"],"award-info":[{"award-number":["U54GM128729"]}]},{"name":"UNDSMHS funds"},{"name":"National Institute of General Medical Sciences of the National Institutes of Health","award":["P20GM103442 and P20GM1113123"],"award-info":[{"award-number":["P20GM103442 and P20GM1113123"]}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:p>The intestinal epithelium requires self-renewal and differentiation in order to function and adapt to pathological diseases such as inflammatory bowel disease, short gut syndrome, and ulcers. The rodent Slfn3 protein and the human Slfn12 analog are known to regulate intestinal epithelial differentiation. Previous work utilizing a pan-Slfn3 knockout (KO) mouse model revealed sex-dependent gene expression disturbances in intestinal differentiation markers, metabolic pathways, Slfn family member mRNA expression, adaptive immune cell proliferation\/functioning genes, and phenotypically less weight gain and sex-dependent changes in villus length and crypt depth. We have now created a Vil-Cre specific Slfn3KO (VC-Slfn3KO) mouse to further evaluate its role in intestinal differentiation. There were increases in Slfn1, Slfn2, Slfn4, and Slfn8 and decreases in Slfn5 and Slfn9 mRNA expression that were intestinal region and sex-specific. Differentiation markers, sucrase isomaltase (SI), villin 1, and dipeptidyl peptidase 4 and glucose transporters, glucose transporter 1 (Glut1), Glut2, and sodium glucose transporter 1 (SGLT1), were increased in expression in VC-Slfn3KO mice based on intestinal region and were also highly female sex-biased, except for SI in the ileum was also increased for male VC-Slfn3KO mice and SGLT1 was decreased for both sexes. Overall, the variations that we observed in these VC-Slfn3KO mice indicate a complex regulation of intestinal gene expression that is sex-dependent.<\/jats:p>","DOI":"10.1371\/journal.pone.0259195","type":"journal-article","created":{"date-parts":[[2021,10,28]],"date-time":"2021-10-28T17:41:48Z","timestamp":1635442908000},"page":"e0259195","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":5,"title":["Vil-Cre specific Schlafen 3 knockout mice exhibit sex-specific differences in intestinal differentiation markers and Schlafen family members expression levels"],"prefix":"10.1371","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3818-5330","authenticated-orcid":true,"given":"Emilie E.","family":"Vomhof-DeKrey","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Allie D.","family":"Stover","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mary","family":"Labuhn","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marcus R.","family":"Osman","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9696-2789","authenticated-orcid":true,"given":"Marc D.","family":"Basson","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"340","published-online":{"date-parts":[[2021,10,28]]},"reference":[{"issue":"1","key":"pone.0259195.ref001","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.gene.2009.07.006","article-title":"Evolution of the Schlafen genes, a gene family associated with embryonic lethality, meiotic drive, immune processes and orthopoxvirus virulence","volume":"447","author":"O Bustos","year":"2009","journal-title":"Gene"},{"issue":"10","key":"pone.0259195.ref002","doi-asserted-by":"crossref","first-page":"1535","DOI":"10.1093\/intimm\/dxh155","article-title":"Modulation of T cell development and activation by novel members of the Schlafen (slfn) gene family harbouring an RNA helicase-like motif","volume":"16","author":"P Geserick","year":"2004","journal-title":"Int Immunol"},{"issue":"35","key":"pone.0259195.ref003","doi-asserted-by":"crossref","first-page":"30723","DOI":"10.1074\/jbc.M500435200","article-title":"Schlafen-1 causes a cell cycle arrest by inhibiting induction of cyclin D1","volume":"280","author":"G Brady","year":"2005","journal-title":"J Biol Chem"},{"issue":"1","key":"pone.0259195.ref004","doi-asserted-by":"crossref","first-page":"62","DOI":"10.1016\/j.bbrc.2008.03.032","article-title":"Subcellular localization of the Schlafen protein family","volume":"370","author":"B Neumann","year":"2008","journal-title":"Biochem Biophys Res Commun"},{"issue":"1","key":"pone.0259195.ref005","doi-asserted-by":"crossref","first-page":"411","DOI":"10.1534\/genetics.105.047118","article-title":"The paternal gene of the DDK syndrome maps to the Schlafen gene cluster on mouse chromosome 11","volume":"172","author":"TA Bell","year":"2006","journal-title":"Genetics"},{"issue":"13","key":"pone.0259195.ref006","doi-asserted-by":"crossref","first-page":"3273","DOI":"10.1016\/j.molimm.2007.03.001","article-title":"Novel transcriptional regulation of the schlafen-2 gene in macrophages in response to TLR-triggered stimulation","volume":"44","author":"WJ Sohn","year":"2007","journal-title":"Mol Immunol"},{"issue":"4","key":"pone.0259195.ref007","doi-asserted-by":"crossref","first-page":"206","DOI":"10.1089\/jir.2012.0133","article-title":"The schlafen family of proteins and their regulation by interferons","volume":"33","author":"E Mavrommatis","year":"2013","journal-title":"J Interferon Cytokine Res"},{"issue":"5","key":"pone.0259195.ref008","doi-asserted-by":"crossref","first-page":"657","DOI":"10.1016\/S1074-7613(00)80663-9","article-title":"Schlafen, a new family of growth regulatory genes that affect thymocyte development","volume":"9","author":"DA Schwarz","year":"1998","journal-title":"Immunity"},{"issue":"3","key":"pone.0259195.ref009","doi-asserted-by":"crossref","first-page":"451","DOI":"10.1189\/jlb.0609410","article-title":"Characterization of Schlafen-3 expression in effector and regulatory T cells","volume":"87","author":"T Condamine","year":"2010","journal-title":"J Leukoc Biol"},{"issue":"1","key":"pone.0259195.ref010","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1002\/cbin.10778","article-title":"The Schlafen family: complex roles in different cell types and virus replication","volume":"42","author":"F Liu","year":"2018","journal-title":"Cell Biol Int"},{"issue":"11","key":"pone.0259195.ref011","doi-asserted-by":"crossref","first-page":"1013","DOI":"10.1001\/jamasurg.2013.3572","article-title":"The correlation between the expression of differentiation markers in rat small intestinal mucosa and the transcript levels of schlafen 3","volume":"148","author":"PL Kovalenko","year":"2013","journal-title":"JAMA Surg"},{"issue":"11","key":"pone.0259195.ref012","doi-asserted-by":"crossref","first-page":"e79745","DOI":"10.1371\/journal.pone.0079745","article-title":"Regulation of epithelial differentiation in rat intestine by intraluminal delivery of an adenoviral vector or silencing RNA coding for Schlafen 3","volume":"8","author":"PL Kovalenko","year":"2013","journal-title":"PLoS One"},{"issue":"4","key":"pone.0259195.ref013","doi-asserted-by":"crossref","first-page":"752","DOI":"10.1016\/j.bbrc.2009.08.094","article-title":"Schlafen-3: a novel regulator of intestinal differentiation","volume":"388","author":"VB Patel","year":"2009","journal-title":"Biochem Biophys Res Commun"},{"issue":"5","key":"pone.0259195.ref014","doi-asserted-by":"crossref","first-page":"598","DOI":"10.1016\/j.amjsurg.2012.07.004","article-title":"Schlafen 3 changes during rat intestinal maturation","volume":"204","author":"MF Walsh","year":"2012","journal-title":"Am J Surg"},{"issue":"6","key":"pone.0259195.ref015","doi-asserted-by":"crossref","first-page":"G994","DOI":"10.1152\/ajpgi.00517.2009","article-title":"Schlafen 3 induction by cyclic strain regulates intestinal epithelial differentiation","volume":"298","author":"L Yuan","year":"2010","journal-title":"Am J Physiol Gastrointest Liver Physiol"},{"issue":"7","key":"pone.0259195.ref016","article-title":"Schlafen 3 knockout mice display gender-specific differences in weight gain, food efficiency, and expression of markers of intestinal epithelial differentiation, metabolism, and immune cell function","volume":"14","author":"EE Vomhof-DeKrey","year":"2019","journal-title":"PLoS One"},{"issue":"12","key":"pone.0259195.ref017","doi-asserted-by":"crossref","first-page":"3029","DOI":"10.1016\/j.bbamcr.2014.09.017","article-title":"The P-loop region of Schlafen 3 acts within the cytosol to induce differentiation of human Caco-2 intestinal epithelial cells","volume":"1843","author":"L Chaturvedi","year":"2014","journal-title":"Biochim Biophys Acta"},{"issue":"1","key":"pone.0259195.ref018","article-title":"Loss of Schlafen3 influences the expression levels of Schlafen family members in ileum, thymus, and spleen tissue","volume":"2020","author":"EE Vomhof-DeKrey","year":"2020","journal-title":"PeerJ"},{"issue":"3","key":"pone.0259195.ref019","doi-asserted-by":"crossref","first-page":"1274","DOI":"10.1159\/000492019","article-title":"Schlafen 12 Interaction with SerpinB12 and Deubiquitylases Drives Human Enterocyte Differentiation","volume":"48","author":"MD Basson","year":"2018","journal-title":"Cell Physiol Biochem"},{"issue":"1","key":"pone.0259195.ref020","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1016\/j.jmoldx.2011.08.002","article-title":"RNAscope: A novel in situ RNA analysis platform for formalin-fixed, paraffin-embedded tissues","volume":"14","author":"F Wang","year":"2012","journal-title":"J Mol Diagnostics"},{"key":"pone.0259195.ref021","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1016\/j.jim.2014.01.014","article-title":"Optimization of murine small intestine leukocyte isolation for global immune phenotype analysis","volume":"405","author":"AW Goodyear","year":"2014","journal-title":"J Immunol Methods"},{"issue":"5 24\u20135","key":"pone.0259195.ref022","article-title":"Dipeptidyl peptidase IV expression in rat jejunal crypt-villus axis is controlled at mRNA level","volume":"261","author":"D Darmoul","year":"1991","journal-title":"Am J Physiol\u2014Gastrointest Liver Physiol"},{"issue":"4 48\u20134","key":"pone.0259195.ref023","article-title":"p27(Kip1) is an inducer of intestinal epithelial cell differentiation","volume":"279","author":"A Quaroni","year":"2000","journal-title":"Am J Physiol\u2014Cell Physiol"},{"issue":"3","key":"pone.0259195.ref024","doi-asserted-by":"crossref","first-page":"553","DOI":"10.1007\/s004410051084","article-title":"Effects of modulation of tyrosine phosphorylation on brush border enzyme activity in human Caco-2 intestinal epithelial cells","volume":"292","author":"MD Basson","year":"1998","journal-title":"Cell Tissue Res"},{"issue":"6","key":"pone.0259195.ref025","doi-asserted-by":"crossref","first-page":"916","DOI":"10.1002\/ijc.2910470622","article-title":"Expression of dipeptidyl aminopeptidase IV during enterocytic differentiation of human colon cancer (Caco\u20102) cells","volume":"47","author":"M Yoshioka","year":"1991","journal-title":"Int J Cancer"},{"issue":"7","key":"pone.0259195.ref026","doi-asserted-by":"crossref","first-page":"1006","DOI":"10.1097\/PAS.0b013e31819f57e9","article-title":"Intestinal differentiation in metaplastic, nongoblet columnar epithelium in the esophagus","volume":"33","author":"HP Hahn","year":"2009","journal-title":"Am J Surg Pathol"},{"issue":"5","key":"pone.0259195.ref027","doi-asserted-by":"crossref","first-page":"1405","DOI":"10.1053\/j.gastro.2017.12.016","article-title":"Villin-1 and Gelsolin Regulate Changes in Actin Dynamics That Affect Cell Survival Signaling Pathways and Intestinal Inflammation","volume":"154","author":"S Roy","year":"2018","journal-title":"Gastroenterology"},{"issue":"1","key":"pone.0259195.ref028","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1074\/jbc.M408858200","article-title":"Peptide YY and neuropeptide Y induce villin expression, reduce adhesion, and enhance migration in small intestinal cells through the regulation of CD63, matrix metalloproteinase-3, and Cdc42 activity","volume":"280","author":"M Lee","year":"2005","journal-title":"J Biol Chem"},{"issue":"1","key":"pone.0259195.ref029","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1177\/002215540505300109","article-title":"Mixed Gastric- and Intestinal-type Metaplasia Is Formed by Cells with Dual Intestinal and Gastric Differentiation","volume":"53","author":"T Niwa","year":"2005","journal-title":"J Histochem Cytochem"},{"issue":"4","key":"pone.0259195.ref030","doi-asserted-by":"crossref","DOI":"10.1152\/ajpgi.00508.2010","article-title":"Constitutive activation of the MEK\/ERK pathway inhibits intestinal epithelial cell differentiation","volume":"301","author":"E Lemieux","year":"2011","journal-title":"Am J Physiol\u2014Gastrointest Liver Physiol"},{"issue":"2","key":"pone.0259195.ref031","article-title":"Engineering of a multicellular organotypic model of the human intestinal mucosa","volume":"141","year":"2011","journal-title":"Gastroenterology"},{"issue":"7","key":"pone.0259195.ref032","doi-asserted-by":"crossref","first-page":"e0219267","DOI":"10.1371\/journal.pone.0219267","article-title":"Schlafen 3 knockout mice display gender-specific differences in weight gain, food efficiency, and expression of markers of intestinal epithelial differentiation, metabolism, and immune cell function","volume":"14","author":"EE Vomhof-DeKrey","year":"2019","journal-title":"PLoS One"},{"issue":"4","key":"pone.0259195.ref033","doi-asserted-by":"crossref","DOI":"10.1152\/ajpgi.90726.2008","article-title":"Schlafen 3, a novel gene, regulates colonic mucosal growth during aging","volume":"296","author":"BB Patel","year":"2009","journal-title":"Am J Physiol\u2014Gastrointest Liver Physiol"},{"issue":"37","key":"pone.0259195.ref034","doi-asserted-by":"crossref","first-page":"25051","DOI":"10.1074\/jbc.M109.030445","article-title":"Role of Schlafen 2 (SLFN2) in the generation of interferon alpha-induced growth inhibitory responses","volume":"284","author":"E Katsoulidis","year":"2009","journal-title":"J Biol Chem"},{"issue":"7422","key":"pone.0259195.ref035","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1038\/nature11433","article-title":"Codon-usage-based inhibition of HIV protein synthesis by human schlafen 11","volume":"491","author":"M Li","year":"2012","journal-title":"Nature"},{"issue":"2","key":"pone.0259195.ref036","doi-asserted-by":"crossref","first-page":"e0212053","DOI":"10.1371\/journal.pone.0212053","article-title":"SLFN11 can sensitize tumor cells towards IFN-\u03b3-mediated T cell killing","volume":"14","author":"R Mezzadra","year":"2019","journal-title":"PLoS One"},{"issue":"3","key":"pone.0259195.ref037","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1515\/bmc.2011.018","article-title":"From mammals to viruses: the Schlafen genes in developmental, proliferative and immune processes","volume":"2","author":"E de la Casa-Esperon","year":"2011","journal-title":"Biomol Concepts"},{"issue":"2","key":"pone.0259195.ref038","first-page":"G136","article-title":"Loss of Slfn3 induces a sex-dependent repair vulnerability after 50% bowel resection","volume":"320","author":"EE Vomhof-DeKrey","year":"2021","journal-title":"Am J Physiol Liver Physiol"},{"issue":"6","key":"pone.0259195.ref039","first-page":"999","article-title":"Schlafen12 reduces the aggressiveness of triple negative breast cancer through post-transcriptional regulation of ZEB1 that drives stem cell differentiation","volume":"53","author":"S Al-Marsoummi","year":"2019","journal-title":"Cell Physiol Biochem"},{"issue":"10","key":"pone.0259195.ref040","doi-asserted-by":"crossref","first-page":"1","DOI":"10.3390\/cancers12102738","article-title":"Schlafen 12 Is Prognostically Favorable and Reduces C-Myc and Proliferation in Lung Adenocarcinoma but Not in Lung Squamous Cell Carcinoma","volume":"12","author":"S Al-Marsoummi","year":"2020","journal-title":"Cancers (Basel)"},{"issue":"7","key":"pone.0259195.ref041","article-title":"Influence of diet and gender on plasma DPP4 activity and GLP-1 in patients with metabolic syndrome: An experimental pilot study","volume":"23","author":"FT P\u00e9rez-Durillo","year":"2018","journal-title":"Molecules"},{"issue":"11","key":"pone.0259195.ref042","first-page":"856","article-title":"Gender differences in the gene expression profiles of glucose transporter GLUT class I and SGLT in mouse tissues","volume":"69","author":"K Nagai","year":"2014","journal-title":"Pharmazie"},{"issue":"7590","key":"pone.0259195.ref043","doi-asserted-by":"crossref","first-page":"344","DOI":"10.1038\/nature16953","article-title":"The sexual identity of adult intestinal stem cells controls organ size and plasticity","volume":"530","author":"B Hudry","year":"2016","journal-title":"Nature"},{"issue":"4","key":"pone.0259195.ref044","doi-asserted-by":"crossref","first-page":"901","DOI":"10.1016\/j.cell.2019.07.029","article-title":"Sex Differences in Intestinal Carbohydrate Metabolism Promote Food Intake and Sperm Maturation","volume":"178","author":"B Hudry","year":"2019","journal-title":"Cell"},{"issue":"5","key":"pone.0259195.ref045","doi-asserted-by":"crossref","first-page":"375","DOI":"10.1038\/nri1604","article-title":"Mechanisms of type-I- and type-II-interferon-mediated signalling","volume":"5","author":"LC Platanias","year":"2005","journal-title":"Nat Rev Immunol"},{"issue":"5164","key":"pone.0259195.ref046","doi-asserted-by":"crossref","first-page":"1415","DOI":"10.1126\/science.8197455","article-title":"Jak-STAT pathways and transcriptional activation in response to IFNs and other extracellular signaling proteins","volume":"264","author":"JE Darnell","year":"1994","journal-title":"Science"},{"issue":"3","key":"pone.0259195.ref047","doi-asserted-by":"crossref","first-page":"361","DOI":"10.1016\/j.immuni.2006.08.014","article-title":"Complex Modulation of Cell Type-Specific Signaling in Response to Type I Interferons","volume":"25","author":"AHH van Boxel-Dezaire","year":"2006","journal-title":"Immunity"},{"key":"pone.0259195.ref048","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1146\/annurev.biochem.67.1.227","article-title":"How cells respond to interferons","volume":"67","author":"GR Stark","year":"1998","journal-title":"Annu Rev Biochem"}],"container-title":["PLOS ONE"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0259195","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,10,28]],"date-time":"2021-10-28T17:42:35Z","timestamp":1635442955000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0259195"}},"subtitle":[],"editor":[{"given":"Arun","family":"Rishi","sequence":"first","affiliation":[],"role":[{"role":"editor","vocabulary":"crossref"}]}],"short-title":[],"issued":{"date-parts":[[2021,10,28]]},"references-count":48,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2021,10,28]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0259195","relation":{},"ISSN":["1932-6203"],"issn-type":[{"type":"electronic","value":"1932-6203"}],"subject":[],"published":{"date-parts":[[2021,10,28]]}}}