Meeting Abstract
129.4 Tuesday, Jan. 7 14:15 Thyroid hormone driving larval cells Mad: the role of c-Myc gene family in intestinal stem cell development MILLER, TC*; WEN, L; CHIU, J; SHI, YS; Eunice Kennedy Shriver National Institute of Child Health and Human Development millertc@mail.nih.gov
During Xenopus (X.) laevis metamorphosis, a remodeling of the larval intestinal epithelium occurs which is analogous the maturation of the mammalian intestine from birth to weaning. Thyroid hormone (TH) is critical for the formation of adult epithelium in the intestine for both mammals and amphibians but the tadpole provides an opportunity to examine the molecular mechanisms of TH action independent of maternal influences. Genome-wide analysis of X. laevis revealed the Max dimerization protein 1 gene that encodes for the Mad protein, a bHLH/Zip transcription factor that competes with cMyc to heterodimerize with Max, was upregulated in the intestinal epithelium during stem cell formation. Previous studies have shown that Mad/Max dimers inhibit transcription leading to differentiation while cMyc/Max binding induces proliferation. qPCR of tissue specific Mad expression confirmed epithelial specific induction during metamorphosis and demonstrated that in both naturally and TH induced metamorphosing intestines, there is strong induction of Mad just prior to cMyc expression and adult stem cell formation. In situ hybridization and immunohistochemical analyses revealed high levels of Mad expression in apoptotic larval cells while cMyc expression is localized in newly forming adult stem cells. Our findings indicate TH induced Mad plays a novel role of initiating or enhancing apoptosis in the maturing intestine, which was further supported by high levels of Mad in other apoptotic tissue. Consequent examination of Mad expression during mouse intestinal development showed transcript levels peaking at birth, further suggesting conservation of function in mammals. Thus, cMyc/Mad balance is likely critical for cell fate determination during TH-dependent, postembryonic adult stem cell development.
