Meeting Abstract

P2.87  Saturday, Jan. 5  Pharmacological suppression of matrixmetalloprotease (MMP) activity with doxycycline inhibits intestinal remodeling and enteric neuronal development during Xenopus laevis metamorphosis DAVIS, T*; KITTS, J; CHAVEZ, A; POND, B; BACHMAN, N; INGALLS, J; TEMKIN, M; HORN, R; MILLER, B; SCHREIBER, A; St. Lawrence University; St. Lawrence University; St. Lawrence University; St. Lawrence University; St. Lawrence University; St. Lawrence University; St. Lawrence University; St. Lawrence University; St. Lawrence University; St. Lawrence University aschreiber@stlawu.edu

Metamorphosis of the herbivorous X. laevis tadpole into a carnivorous frog is accompanied by an abrupt remodeling of the gut: the intestine shortens in length by 75%, the connective tissue and smooth muscle layers thicken, enteric neuronal cell bodies form clusters and have increased axon cable diameter, and the lumen becomes highly involuted. Virtually all aspects of amphibian metamorphosis are mediated by thyroid hormone (TH), and the mRNAs of several matrixmetalloprotease (MMPs) are known to be upregulated directly (i.e. stromelysin-3) or indirectly (e.g. gelatinase A and MT1-MMP) in the mesenchyme of the small intestine by TH. Although the kinetics of intestinal MMP mRNA expression have been studied extensively in the amphibian model and shown to correlate with gut remodeling, the influence of actual MMP enzymatic activity on intestinal remodeling has not been well-described. Here we show that treatment of pre-metamorphic tadpoles (Nieuwkoop and Faber stage 50 and 54) with a broad-spectrum inhibitor of MMP activity (doxycycline) inhibits virtually all aspects of intestinal remodeling, including shortening, thickening of the mesenchyme and smooth muscle layers, enteric neuronal clustering and changes in axonal cable diameter, and development of involutions on the lumen compared with controls following treatment with TH (3 nM triiodothyronine) for 4 days. Concurrent treatment with doxycycline and TH did not, however, inhibit upregulation of mRNA for stromelysin-3 (a TH direct-response MMP). These findings directly support the hypothesis that an upregulation of TH-responsive MMP activity during metamorphosis mediates diverse changes that accompany intestinal remodeling.