This study builds on earlier work in the lab establishing roles for physical forces in chick gut morphogenesis. One critical aspect of gut formation that is largely driven by mechanical forces is the coiling of the loops of the intestine. This process occurs when the primitive gut tube grows faster than the attached dorsal mesentery, an elastic tissue that gets stretched and hence, exerts an isotropic force on the gut tube along its length. The tightness of the coiling of the gut is proportional to this force and hence, to the difference in the relaxed lengths of the gut tube and dorsal mesentery. Thus, the differential growth of the two tissues determines the looping pattern of the gut. A key question thus becomes, what establishes the different in growth rates of these tissues? In Aim 1, we investigate the role of the secreted protein BMP2 in establishing this differential growth. BMP2 is expressed in the developing gut. Blocking BMP2 function causes a decrease in looping, while the excessive BMP activity increases the number and curvature of the loops.
The first aim will quantify the effect of BMP activity on morphometric and biophysical parameters. Computational modeling will be used to identify the key biophysical determinants in this system. A second aspect of gut development, that is also dependent on physical forces, is the buckling of the intestinal lumen to generate villi. In this process, buckling forces are generated through confined growth of the epithelium at a time when expansion is constrained by the adjacent differentiating smooth muscle. In other segments of the gut (esophagus, colon, etc.) there are significant differences in the thickness and timing of smooth muscle differentiation. Experiments in Aim 2 determine the extent to which these differences in smooth muscle architecture and dynamics are responsible for the distinct epithelial morphology of the fore-and hind guts. Drugs will be employed to block smooth muscle differentiation to test their necessity. Morphometric and biophysical parameters will be measured and entered into computational models to test the degree to which epithelial morphology can be entirely explained on this basis.
Defects in gut formation lead to serious birth defects. This study will shed light on how the digestive tract attains its proper shape and structure, allowing i to perform its key functions in absorbing nutrients.
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|Nerurkar, Nandan L; Mahadevan, L; Tabin, Clifford J (2017) BMP signaling controls buckling forces to modulate looping morphogenesis of the gut. Proc Natl Acad Sci U S A 114:2277-2282|