Vil-Cre specific Schlafen 3 knockout mice exhibit sex-specific differences in intestinal differentiation markers and Schlafen family members expression levels

Abstract

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.

Schlafen Family Intra-Regulation by IFN-α2 in Triple-Negative Breast Cancer

“…These results cohere with previous work suggesting that loss of the mouse SLFN12 ortholog, Slfn3, can affect the expression of the other SLFN members. In mice, the loss of Slfn3 changes the expression of other murine Slfn family members in the intestinal mucosa, thymus, and spleen in a complex fashion [17]. The loss of Slfn3 also influences the expression of other Schlafen family members after 50% bowel resection in mice in a sex-dependent manner [17,18].…”

“…In mice, the loss of Slfn3 changes the expression of other murine Slfn family members in the intestinal mucosa, thymus, and spleen in a complex fashion [17]. The loss of Slfn3 also influences the expression of other Schlafen family members after 50% bowel resection in mice in a sex-dependent manner [17,18].…”

“…It seems paradoxical that preventing the effect of IFN-α2 on SLFN14 blocked the IFN-α2 effect on cell viability, but reducing all the SLFN proteins only resulted in a partial recovery [27,28]. Conversely, the SLFN family members may function as an intra-regulated rheostat with some redundancy in expressions and function since the SLFN paralogues are clustered together and have some structural similarity [17,[30][31][32]. The SLFN family members may require a balanced expression to maintain or decrease cell viability.…”

“…Unfortunately, it was not possible to design a single siRNA to interfere with the expression of all the SLFN family members because they lack a common sequence that can be targeted by this method; therefore, we used individually targeted siRNAs (Supplemental Tables S3 and S4) [17,18]. We used siRNA targeting SLFN5, SLFN12-Like, and SLFN14 to further examine the relationship of the SLFN family members that were synergistically induced by IFN-α2 and AdvShSLFN12 in TNBC.…”

RNA Sequencing of Intestinal Enterocytes Pre- and Post-Roux-en-Y Gastric Bypass Reveals Alteration in Gene Expression Related to Enterocyte Differentiation, Restitution, and Obesity with Regulation by Schlafen 12

“…We previously studied the role of SLFN12 (and its mouse ortholog, Slfn3) in the regulation of enterocyte differentiation [ 7 , 8 , 9 , 10 , 11 , 12 , 13 ]. SLFN12 is one of a family of proteins that also regulate hematopoiesis, the immune response, and bone biology [ 14 , 15 , 16 , 17 ].…”