Browsing by Author "Garg, Ankur"

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    Alx4 relays sequential FGF signaling to induce lacrimal gland morphogenesis
    (PLOS, 2017-10-13) Garg, Ankur; Bansal, Mukesh; Gotoh, Noriko; Feng, Gen-Sheng; Zhong, Jian; Wang, Fen; Kariminejad, Ariana; Brooks, Steven; Zhang, Xin; Biochemistry and Molecular Biology, School of Medicine
    The sequential use of signaling pathways is essential for the guidance of pluripotent progenitors into diverse cell fates. Here, we show that Shp2 exclusively mediates FGF but not PDGF signaling in the neural crest to control lacrimal gland development. In addition to preventing p53-independent apoptosis and promoting the migration of Sox10-expressing neural crests, Shp2 is also required for expression of the homeodomain transcription factor Alx4, which directly controls Fgf10 expression in the periocular mesenchyme that is necessary for lacrimal gland induction. We show that Alx4 binds an Fgf10 intronic element conserved in terrestrial but not aquatic animals, underlying the evolutionary emergence of the lacrimal gland system in response to an airy environment. Inactivation of ALX4/Alx4 causes lacrimal gland aplasia in both human and mouse. These results reveal a key role of Alx4 in mediating FGF-Shp2-FGF signaling in the neural crest for lacrimal gland development., The dry eye disease caused by lacrimal gland dysgenesis is one of the most common ocular ailments. In this study, we show that Shp2 mediates the sequential use of FGF signaling in lacrimal gland development. Our study identifies Alx4 as a novel target of Shp2 signaling and a causal gene for lacrimal gland aplasia in humans. Given this result, there may also be a potential role for Alx4 in guiding pluripotent stem cells to produce lacrimal gland tissue. Finally, our data reveals an Alx4-Fgf10 regulatory unit broadly conserved in the diverse array of terrestrial animals from humans to reptiles, but not in aquatic animals such as amphibians and fish, which sheds light on how the lacrimal gland arose as an evolutionary innovation of terrestrial animals to adapt to their newfound exposure to an airy environment.
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    Lacrimal gland development: From signaling interactions to regenerative medicine
    (Wiley, 2017-12) Garg, Ankur; Zhang, Xin; Biochemistry and Molecular Biology, School of Medicine
    The lacrimal gland plays a pivotal role in keeping the ocular surface lubricated, and protecting it from environmental exposure and insult. Dysfunction of the lacrimal gland results in deficiency of the aqueous component of the tear film, which can cause dryness of the ocular surface, also known as the aqueous-deficient dry eye disease. Left untreated, this disease can lead to significant morbidity, including frequent eye infections, corneal ulcerations, and vision loss. Current therapies do not treat the underlying deficiency of the lacrimal gland, but merely provide symptomatic relief. To develop more sustainable and physiological therapies, such as in vivo lacrimal gland regeneration or bioengineered lacrimal gland implants, a thorough understanding of lacrimal gland development at the molecular level is of paramount importance. Based on the structural and functional similarities between rodent and human eye development, extensive studies have been undertaken to investigate the signaling and transcriptional mechanisms of lacrimal gland development using mouse as a model system. In this review, we describe the current understanding of the extrinsic signaling interactions and the intrinsic transcriptional network governing lacrimal gland morphogenesis, as well as recent advances in the field of regenerative medicine aimed at treating dry eye disease.
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    Reiterative FGF signaling determines the identity and morphology of the lacrimal gland
    (2017-12) Garg, Ankur; Shou, Weinian
    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.