Mastermind-like transcriptional co-activator-mediated Notch signaling is indispensable for maintaining conjunctival epithelial identity

Zhang, Yujin; Lam, Oliver; Nguyen, Minh‐Thanh; Ng, Gracia Y.; Pear, Warren S.; Ai, Walden; Wang, I‐Jong; Kao, Winston W.‐Y.; Liu, Chia-Yang

doi:10.1242/dev.082842

“…Alternatively, it was proposed that some of the Notch-related corneal phenotypes represent secondary effects caused by disruption of the Notch pathway in other tissues of the ocular surface. Supporting this possibility is the evidence that ectopic expression of the dominant-negative form of the transcriptional co-activator Maml1 in K14-expressing cells prevents the differentiation of conjunctival goblet cells (Zhang et al, 2013). As normal levels of Muc5ac are expressed at the conjunctiva of K14Ift88 cKO mice, we conclude that goblet cell differentiation and function are not affected by the absence of cilia (Fig.…”

Section: Corneal Thickening and Proliferationsupporting

confidence: 54%

Primary cilia maintain corneal epithelial homeostasis by regulation of the Notch signaling pathway

Grisanti¹,

Revenkova²,

Gordon³

et al. 2016

Journal of Cell Science

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Primary cilia have been linked to signaling pathways involved in cell proliferation, cell motility and cell polarity. Defects in ciliary function result in developmental abnormalities and multiple ciliopathies. Patients affected by severe ciliopathies, such as Meckel syndrome, present several ocular surface disease conditions of unclear pathogenesis. Here, we show that primary cilia are predominantly present on basal cells of the mouse corneal epithelium (CE) throughout development and in the adult. Conditional ablation of cilia in the CE leads to an increase in proliferation and vertical migration of basal corneal epithelial cells (CECs). A consequent increase in cell density of suprabasal layers results in a thicker than normal CE. Surprisingly, in cilia-deficient CE, cilia-mediated signaling pathways, including Hh and Wnt pathways, were not affected but the intensity of Notch signaling was severely diminished. Although Notch1 and Notch2 receptors were expressed normally, nuclear Notch1 intracellular domain (N1ICD) expression was severely reduced. Postnatal development analysis revealed that in ciliadeficient CECs downregulation of the Notch pathway precedes cell proliferation defects. Thus, we have uncovered a function of the primary cilium in maintaining homeostasis of the CE by balancing proliferation and vertical migration of basal CECs through modulation of Notch signaling.

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“…Tgfbr2 conditional deletion in K14-expressing cells results in progressive periorbital tissue expansion with narrowing of the palpebral fissure Murine ocular surface epithelium is derived from K14-expressing cells (Pajoohesh-Ganji et al, 2012;Zhang et al, 2013). Mice that lack Tgfbr2 in stratified epithelia expressing K14 (cKO mice; K14-Cre×Tgfbr2 flox/flox ), including skin, oral and anogenital epithelia, are susceptible to squamous cell carcinoma formation (Lu et al, 2006;Guasch et al, 2007).…”

Section: Resultsmentioning

confidence: 99%

“…Within the conjunctiva, goblet cells secrete aqueous mucins that protect the surface of the eye by contributing to the tear film to maintain lubrication, clear molecules and maintain mucosal barrier integrity (Wei et al, 1993;Mantelli and Argueso, 2008). Abnormalities in goblet cell function are associated with dry eye syndrome and other drying diseases (Mantelli and Argueso, 2008;Marko et al, 2013;Zhang et al, 2013), and lead to perturbations of the ocular surface epithelium that negatively affect eye health and vision. Mechanisms that regulate goblet cell differentiation in the conjunctiva are not well understood, thereby limiting therapeutic options for ocular surface disorders, such as dry eye syndrome, largely to analgesic measures, such as artificial tears (Cornec et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

TGFβ signaling inhibits goblet cell differentiation via SPDEF in conjunctival epithelium

McCauley

¹

,

Liu

²

,

Attia

³

et al. 2014

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The ocular surface epithelia, including the stratified but nonkeratinized corneal, limbal and conjunctival epithelium, in concert with the epidermal keratinized eyelid epithelium, function together to maintain eye health and vision. Abnormalities in cellular proliferation or differentiation in any of these surface epithelia are central in the pathogenesis of many ocular surface disorders. Goblet cells are important secretory cell components of various epithelia, including the conjunctiva; however, mechanisms that regulate goblet cell differentiation in the conjunctiva are not well understood. Herein, we report that conditional deletion of transforming growth factor β receptor II (Tgfbr2) in keratin 14-positive stratified epithelia causes ocular surface epithelial hyperplasia and conjunctival goblet cell expansion that invaginates into the subconjunctival stroma in the mouse eye. We found that, in the absence of an external phenotype, the ocular surface epithelium develops properly, but young mice displayed conjunctival goblet cell expansion, demonstrating that TGFβ signaling is required for normal restriction of goblet cells within the conjunctiva. We observed increased expression of SAM-pointed domain containing ETS transcription factor (SPDEF) in stratified conjunctival epithelial cells in Tgfbr2 cKO mice, suggesting that TGFβ restricted goblet cell differentiation directly by repressing Spdef transcription. Gain of function of Spdef in keratin 14-positive epithelia resulted in the ectopic formation of goblet cells in the eyelid and peripheral cornea in adult mice. We found that Smad3 bound two distinct sites on the Spdef promoter and that treatment of keratin 14-positive cells with TGFβ inhibited SPDEF activation, thereby identifying a novel mechanistic role for TGFβ in regulating goblet cell differentiation.

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“…Interestingly, in the ocular surface Notch activation contributes to the maintenance of the stratified and non-keratinized corneal and conjunctival cells differentiation and function (Djalilian et al, 2008;Ma et al, 2011;Nakamura et al, 2008;Vauclair et al, 2007;Xiong et al, 2011;Zhang et al, 2013). This led us to hypothesize that primary cilia could play an important role in maintaining CE homeostasis and/or morphogenesis.…”

Section: Introductionmentioning

confidence: 99%

Primary cilia maintain corneal epithelial homeostasis by regulation of the Notch signaling pathway

Grisanti

¹

,

Revenkova

²

,

Gordon

³

et al. 2016

View full text Add to dashboard Cite

Primary cilia have been linked to signaling pathways involved in cell proliferation, cell motility and cell polarity. Defects in ciliary function result in developmental abnormalities and multiple ciliopathies. Patients affected by severe ciliopathies, such as Meckel syndrome, present several ocular surface disease conditions of unclear pathogenesis. Here, we show that primary cilia are predominantly present on basal cells of the mouse corneal epithelium (CE) throughout development and in the adult. Conditional ablation of cilia in the CE leads to an increase in proliferation and vertical migration of basal corneal epithelial cells (CECs). A consequent increase in cell density of suprabasal layers results in a thicker than normal CE. Surprisingly, in cilia-deficient CE, cilia-mediated signaling pathways, including Hh and Wnt pathways, were not affected but the intensity of Notch signaling was severely diminished. Although Notch1 and Notch2 receptors were expressed normally, nuclear Notch1 intracellular domain (N1ICD) expression was severely reduced. Postnatal development analysis revealed that in ciliadeficient CECs downregulation of the Notch pathway precedes cell proliferation defects. Thus, we have uncovered a function of the primary cilium in maintaining homeostasis of the CE by balancing proliferation and vertical migration of basal CECs through modulation of Notch signaling.

show abstract

Mastermind-like transcriptional co-activator-mediated Notch signaling is indispensable for maintaining conjunctival epithelial identity

Cited by 37 publications

References 64 publications

Primary cilia maintain corneal epithelial homeostasis by regulation of the Notch signaling pathway

Primary cilia maintain corneal epithelial homeostasis by regulation of the Notch signaling pathway

TGFβ signaling inhibits goblet cell differentiation via SPDEF in conjunctival epithelium

Primary cilia maintain corneal epithelial homeostasis by regulation of the Notch signaling pathway

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