| Summary: | Indiana University-Purdue University Indianapolis (IUPUI) === The lacrimal gland plays an essential role in protection of the ocular surface by secreting
the aqueous component of the tear film. Deficiency in the lacrimal gland is the main
cause of dry eye disease, but existing treatments only alleviate the symptoms without
curing the underlying disease. To develop curative measures, a thorough understanding
of lacrimal gland development is needed. Lacrimal gland is formed as a result of
interaction between the neural crest-derived mesenchyme and the conjunctival
epithelium. The mesenchyme secretes the chemo-attractive signal of Fgf10, which binds
to epithelial Fgfr2b and co-receptor heparan sulphate proteoglycans, to promote budding
and branching morphogenesis of the lacrimal gland. However, the mechanism by which
Fgf10 expression is regulated within the neural crest and the direct downstream targets of
Fgf signaling in the epithelium are currently unknown. In this study, we show that FGF
signaling mediated by protein phosphatase Shp2 is required for the proper patterning and
differentiation of the neural crest-derived mesenchyme to produce Fgf10. Genetic
evidence further demonstrates that Shp2 is recruited by Frs2α to activate Ras-MAPK
signaling downstream to Fgfr1 and Fgfr2 but not to Pdgfrα in the neural crest. By
differential gene expression analysis, we identified homeodomain transcription factor
Alx4 as the key effector of Shp2 signaling to control expression of Fgf10 in the
periocular mesenchyme. Loss of function ALX4/Alx4 mutation disrupted lacrimal gland
development in both human and mouse. Our results reveal a FGF-Shp2-Alx4-Fgf10 axis
in regulating neural crests during lacrimal gland development. In addition, we also show
that Fgf signaling cascade mediated by Pea3 family of transcription factors are critical for
lacrimal gland duct elongation and branching. High-throughput gene expression analysis
revealed that Pea3 genes were important for establishing the tissue identity of the
lacrimal gland. Loss of Pea3 resulted in upregulation of Notch signaling with the
concomitant loss in the expression of the members of Six family of transcription factors
and a switch of cell fate to the epidermal skin-like cells. These findings show that Fgf signaling is used reiteratively to establish the identity of both the epithelium and
mesenchyme of the lacrimal gland. === 2 years
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