Submitted to: Molecular and Cellular Biology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 3/22/2007
Publication Date: 6/15/2007
Citation: Simmen, F.A., Xiao, R., Velarde, M.C., Nicholson, R.D., Bowman, M., Fujii-Kuriyama, Y., Oh, P.S., Simmen, R. 2007. Dysregulation of crypt cell proliferation and lineage determination, and villus cell migration in the small intestines of mice lacking the intestinal smooth muscle-expressed transcription factor, Krüppel-like factor 9 (Klf9). Molecular and Cellular Biology. 292(6):1757-1769.
Interpretive Summary: Proper nutrition of neonates and adolescents is dependent on appropriate development of the small intestine. The molecular mechanisms by which gut development is regulated in concert with other organ systems are unknown. What is known, however, is that malfunctions in this process often underlie poor growth and development in infants and children. In this report, we identify a gene (named Klf9) that stimulates tissue growth of small intestine in the mouse and also describe how it does this action. Our results suggest that many other genes that control cell division and cell migration are affected by Klf9, which serves as master regulator, and that Klf9 may provide a starting point for understanding how to promote gut growth by nutritional means when this is otherwise compromised.
Technical Abstract: Krüppel-like factor 9 (Klf9), a zinc-finger transcription factor, is implicated in the control of cell proliferation, cell differentiation and cell fate. Mice with targeted inactivation of Klf9 gene exhibit postnatal growth retardation and increased mortality after birth. Using these mice, we have investigated the involvement of Klf9 in small intestine crypt-villus cell renewal and lineage determination. We report the predominant expression of Klf9 gene in small intestine smooth muscle (muscularis externa). Jejunums null for Klf9 have shorter villi, reduced crypt transit cell proliferation, and altered lineage determination as indicated by decreased and increased numbers of Goblet and Paneth cells, respectively. A stimulatory role for Klf9 in villus cell migration was confirmed by BrdU labeling. Downstream (direct and indirect) gene targets of jejunum Klf9 included effectors of Wnt signaling (Pitx2, Ccnd2, Ryk), Ptk-6 and Igfbp4. Results suggest that Klf9 controls the elaboration, from small intestine smooth muscle, of molecular mediator(s) of crypt transit cell proliferation and lineage determination, and villus cell migration.