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Helen P. Makarenkova, Anastasia Gromova, Robyn Meech; Molecular Mechanisms of Lacrimal Gland Morphogenesis: Mechanism of Lacrimal Bud Elongation. Invest. Ophthalmol. Vis. Sci. 2011;52(14):3708.
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© ARVO (1962-2015); The Authors (2016-present)
Despite the frequency of dry eye syndrome and other lacrimal gland disorders, relatively little is known about the development and physiology of the lacrimal gland. We are focusing on understanding the regulatory mechanisms that control lacrimal gland (LG) branching and repair.
In this study we have examined the LG development using ex vivo LG cultures, q-RT-PCR and RT²ProfilerTM PCR microarrays.
We are investigating how the molecular structure of different FGFs is translated into specific cellular responses and how FGF signals are integrated into signaling network with other molecules that regulate LG morphogenesis. LG bud growth is regulated by members of the FGF7 subfamily (FGF3, 7 and 10). Although all three these FGFs signal through the same epithelially expressed FGFR2b, they have different effects on LG morphogenesis. We have recently linked the observed and reported differences in the structural biology of FGF7 subfamily members with their unique biologic activity in branching morphogenesis and investigated the downstream signaling events and cooperation of FGFs with other important regulators of epithelial bud migration. Thus we show that differences in the binding of FGF3, FGF7, and FGF10 to heparan sulfate (HS) within the extracellular matrix results in the formation of different gradients that regulate cell proliferation and differentiation and shape of migrating LG bud. Thus, FGF3 forms a much sharper gradient than FGF7 or FGF10 and this gradient does not maintain distal bud formation within a migrating epithelial explant. Moreover, application of FGF3 does not induce cell proliferation within the LG epithelial explant and FGF3, but not FGF10, induces mesenchymal cell aggregations. We also found that FGF10 induces longer MAPK/ERK1/2 activation than FGF3, and that the length of MAPK (Erk1,2) activation contributes to the speed of LG epithelial bud migration. Our recent studies also suggest a critical role for the homeobox transcription factor Barx2 in LG bud migration. Thus we found that Barx2 and FGF10 cooperate to regulate of expression of matrix metalloproteinases (MMPs) that are required for epithelial bud growth.
Our study has determined a regulatory connection between FGFs, MAPK activation, and the transcription factor Barx2 in regulation of LG bud elongation. We have also dissected the origin of the differential functions of FGFs, which will allow us to define the general mechanisms of LG morphogenesis and repair.
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