Our long term objective is to study how ectodermal organ size is determined. In the last funding period, we studied the regulation of organ size and shape in feather, hair, beak, tooth, etc. We developed the topobiological concept of localized growth zone (LoGZ), suggesting the number, size, position and activity of clustered transient amplifying (TA) cells can determine an organ's size and shape. In this renewal, we ask what unique characteristics in hairs and feathers enable them to increase in size and regenerate continuously throughout adult life. We hypothesize it is made possible by forming a sustaining growth unit, composed of epidermal stem / TA / differentiated cells and a dermal signaling center, topologically arranged in a follicle design that allows the continuous flow of growth and regeneration without structural constraints. Using the feather model, we postulate that FGF / MARK is the major driving force of cell proliferation for size increases throughout bud and follicle stages. Organized growth is essential in organ building and tissue engineering. In the upward feather bud outgrowth, the Notch pathway may specify a growth - maturation gradient to the feather filament growth zone, conferring orientation to the elongating feather buds (Aim 1). In the downward follicle wall invagination, the dermal papilla may work as a signaling center to direct the epithelial tongue extension via FGF 10 (Aim 2). In the growing follicle, FGF activity is modulated by sprouty and antagonized by BMP to generate different structures along the feather axis (Aim 3). Preliminary microarray data are consistent with these candidate pathways. Efforts are made to alter dermal papilla properties so we can convert small feathers into large ones via modulation of the stem cell microenvironment, rather than stem cells themselves (Aim 4). RCAS retroviral vectors, siRNAs, electroporation, protein coated beads, chicken/quail chimeric explant, follicle dermal papilla transplantations, Oil tracing, time lapse movies, microarrays, bioinformatics analyses, etc. are the techniques we will apply to these studies. Using this excellent animal model, we will identify gene pathways critical for follicle morphogenesis and essential topobiological principles for this process. We should learn the developmental origin of appendage stem cells and dermal papilla. The knowledge acquired can be directed to make short hairs grow longer, and to engineer ectodermal stem cells into follicles with sustaining growth ability.
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