Abstract
Self-renewal and differentiation are essential for intestinal epithelium absorptive functioning and adaptation to pathological states such as short gut syndrome, ulcers, and inflammatory bowel disease. The rodent Slfn3 and its human analog Slfn12 are critical in regulating intestinal epithelial differentiation. We sought to characterize intestinal function in Slfn3 knockout (KO) mice. Male and female pair-fed Slfn3KO mice gained less weight with decreased food efficiency than wild type (WT) mice, with more pronounced effects in females. RNA sequencing performed on intestinal mucosa of Slfn3KO and WT mice showed gene ontology decreases in cell adhesion molecule signaling, tumor necrosis factor receptor binding, and adaptive immune cell proliferation/functioning genes in Slfn3KO mice, with greater effects in females. qPCR analysis of fatty acid metabolism genes, Pla2g4c, Pla2g2f, and Cyp3c55 revealed an increase in Pla2g4c, and a decrease in Pla2g2f in Slfn3KO females. Additionally, adipogenesis genes, Fabp4 and Lpl were decreased and ketogenesis gene Hmgcs2 was increased in female Slfn3KO mice. Sequencing did not reveal significant changes in differentiation markers, so qPCR was utilized. Slfn3KO tended to have decreased expression of intestinal differentiation markers sucrase isomaltase, dipeptidyl peptidase 4, villin 1, and glucose transporter 1 (Glut1) vs. WT males, although these trends did not achieve statistical significance unless data from several markers was pooled. Differentiation markers, Glut2 and sodium-glucose transporter 1 (SGLT1), did show statistically significant sex-dependent differences. Glut2 mRNA was reduced in Slfn3KO females, while SGLT1 increased in Slfn3KO males. Notch2 and Cdx2 were only increased in female Slfn3KO mice. Although Slfn3KO mice gain less weight and decreased food efficiency, their biochemical phenotype is more subtle and suggests a complex interplay between gender effects, Slfn3, and another regulatory pathway yet to be identified that compensates for the chronic loss of Slfn3.
Highlights
The ability of the intestinal epithelium for self-renewal and differentiation is essential for both normal absorptive function and intestinal adaptation to pathological states such as fasting, ileus, short gut syndrome, intestinal ulcers, and intestinal bowel disease, as well as changes in diet
Female Slfn3 knockout (Slfn3KO) mice consumed less food than female wild type (WT) mice (Fig 1C), but when the food efficiency was calculated to correct for the food intake, there was a greater decrease in the food efficiency of the Slfn3KO animals in comparison to the WT (Fig 1D)
The muscularis externa thickness was increased by 2.353 ± 0.448 μm in the male Slfn3KO mice in comparison to the male WT mice whereas the female Slfn3KO mice had a decrease in muscularis externa thickness by 2.52 ± 0.330 μm (Fig 2C)
Summary
The ability of the intestinal epithelium for self-renewal and differentiation is essential for both normal absorptive function and intestinal adaptation to pathological states such as fasting, ileus, short gut syndrome, intestinal ulcers, and intestinal bowel disease, as well as changes in diet. Several signaling pathways act in a combinatorial manner to regulate normal intestinal epithelium homeostasis. These include the Wnt pathway, the Notch pathway, the Hedgehog system, members of the transforming growth factor- β family, and the phosphoinositide 3-kinase pathway [1]. Group III, the long Slfns, include Slfn5, -8, -9, and -14[2, 3]. Groups II and III contain another Slfn specific domain, the SWADL domain (Ser-Trp-Ala-Asp-Leu). Much is known about the other Slfn proteins and the roles they play in immune cell development, cancer cell function, differentiation in hematopoietic cell lines, and regulation of viral replication, the role of Slfn has been less well understood[2, 3, 8,9,10,11]
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