Theme B: Epithelial Growth Control Theme Leader: Calof Other Faculty: Lander, Nie, Lowengrub, Wan, Mjolsness, Yu Background and Significance Epithelia are the fundamental building blocks of all animal tissues. They consist of sheets of closely packed cells with evident polarity along one axis (the apical-basal axis, orthogonal to the plane of the epithelium). Typically, epithelial cells are produced through stereotyped lineages, and cells at different lineage stages adopt different positions. Thus, in stratified (multilayered) epithelia, lineage stage often correlates with distance from the basal surface of the epithelium. Here we consider a performance objective common to many epithelia: precise self-regulation of growth and size. In a variety of experimental paradigms, epithelia seem to """"""""know"""""""" when to stop growing, both during development and when participating in tissue regeneration. Failures in this process underlie diseases as diverse as psoriasis and cancer. A long-standing model of growth control is based on the notion of a simple paracrine (or endocrine) feedback loop, in which differentiated cells at the end of a lineage secrete a factor that inhibits the divisions of the progenitor cells that make them (Bullough, 1965). However, in deuterostomes (e.g. vertebrates), the growth and differentiation of epithelia is clearly also controlled by signals from underlying connective tissue, or stroma (Watt, 2001; Fuchs et al., 2004). The research described in Theme B focuses on growth control in two very different epithelia: the mammalian olfactory epithelium (OE)?the sensory epithelium in the nasal cavity that contains neurons that transmit the sense of smell to the brain?and the epithelium of the wing imaginal disc of the fruit fly Drosophila larva. In both cases, the fundamental question is the same: how does the system grow at the """"""""right"""""""" rate, and stop growing when it reaches the """"""""right"""""""" size? The context in which this question is asked, however, is very different in the two cases. In the OE, a stratified epithelium, the growth axis in question is apico-basal, i.e. we are interested in control of the thickness of the epithelium;in the wing disc the growth in question is in the plane of the epithelium, i.e. we are interested in the expansion of the epithelial sheet. Interestingly, we shall argue that critical factors in both cases are spatially-graded distributions of molecules belonging to the TGF-beta superfamily. In this sense, the problems discussed in this theme potentially overlap with the morphogen gradient problems of Theme A. However, the fact that the output of the systems discussed in this aim concerns proliferative dynamics gives them a distinctive character.
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