Conditional disruption of mouse Klf5 results in defective eyelids with malformed meibomian glands, abnormal cornea and loss of conjunctival goblet cells

Kenchegowda, Doreswamy; Gupta, Divya; Wan, Hang; Whitsett, Jeffrey A.; Swamynathan, Sudha

doi:10.1016/j.ydbio.2011.05.005

Cited by 59 publications

(66 citation statements)

References 54 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…It has previously been reported that the conditional knockout of Krüppel-like factors 4 or 5 (Klf4 or Klf5) in the ocular surface epithelia with Le-Cre driver also caused a failure of goblet cell formation (Swamynathan et al, 2007;Kenchegowda et al, 2011). This result prompted us to test whether dnMaml1 could impact the expression of Klf4 and Klf5.…”

Section: Dnmaml1 Downregulated Expression Of Krüppel-like Factors Andmentioning

confidence: 99%

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

et al. 2013

View full text Add to dashboard Cite

SUMMARYConjunctival goblet cells primarily synthesize mucins to lubricate the ocular surface, which is essential for normal vision. Notch signaling has been known to associate with goblet cell differentiation in intestinal and respiratory tracts, but its function in ocular surface has yet to be fully characterized. Herein, we demonstrate that conditional inhibition of canonical Notch signaling by expressing dominant negative mastermind-like 1 (dnMaml1) in ocular surface epithelia resulted in complete suppression of goblet cell differentiation during and subsequent to development. When compared with the ocular surface of wild-type mice (OS Wt ), expression of dnMaml1 at the ocular surface (OS dnMaml1 ) caused conjunctival epithelial hyperplasia, aberrant desquamation, failure of Mucin 5ac (Muc5ac) synthesis, subconjunctival inflammation and epidermal metaplasia in cornea. In addition, conditional deletion of Notch1 from the ocular surface epithelia partially recapitulated OS dnMaml1 phenotypes. We have demonstrated that N1-ICD (Notch1 intracellular domain) transactivated the mouse Krüppel-like factor 4 (Klf) promoter and that Klf4 directly bound to and significantly potentiated the Muc5ac promoter. By contrast, OS dnMaml1 dampened Klf4 and Klf5 expression, and diminished Muc5ac synthesis. Collectively, these findings indicated that Maml-mediated Notch signaling plays a pivotal role in the initiation and maintenance of goblet cell differentiation for normal ocular surface morphogenesis and homeostasis through regulation of Klf4 and Klf5.

show abstract

Section: Dnmaml1 Downregulated Expression Of Krüppel-like Factors Andmentioning

confidence: 99%

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

et al. 2013

View full text Add to dashboard Cite

show abstract

“…Although the role of Spdef in goblet cell differentiation is consistent between the lung, the intestine and the conjunctiva, transcriptional control of Spdef remains unclear, especially in the conjunctiva. Conditional deletion of Klf4 (Swamynathan et al, 2007;Gupta et al, 2011) or Klf5 (Kenchegowda et al, 2011), which are structurally related and expressed in the ocular surface epithelium, results in a loss of conjunctival goblet cells and reduced Spdef mRNA expression Marko et al, 2013). Gene expression analysis of Klf4-deficient mice yielded Spdef, but not elements of the TGFβ signaling pathway, as direct targets of KLF4 in the conjunctiva .…”

Section: Tgfβ Is a Novel Regulator Of Spdefmentioning

confidence: 99%

“…Although the precise regulatory networks governing goblet cell differentiation in the conjunctiva are unknown, conjunctival phenotypes in murine models have identified Krüppel-like family 4 (KLF4) (Swamynathan et al, 2007;Gupta et al, 2011) and 5 (KLF5) (Kenchegowda et al, 2011), SAM pointed domaincontaining ETS transcription factor (SPDEF) (Marko et al, 2013) and the Notch signaling pathway as essential factors required for goblet cell differentiation in the mouse conjunctiva, as deletion of these genes, or inhibition of Notch signaling, results in conjunctiva that lack goblet cells. SPDEF plays a crucial role in goblet cell differentiation in multiple organs, including the lung (Park et al, 2007), the intestine Noah et al, 2010) and the conjunctiva (Marko et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

TGFβ signaling inhibits goblet cell differentiation via SPDEF in conjunctival epithelium

et al. 2014

View full text Add to dashboard Cite

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.

show abstract

“…Foxc1 mediates the BMP signaling required for lacrimal gland development (Mattiske et al, 2006). Klf5 conditional null lacrimal glands showed a disrupted acinar organization (Kenchegowda et al, 2011) and Six1 −/− fetuses displayed small lacrimal glands (Laclef et al, 2003). However, little is known about the mechanisms required to initiate lacrimal gland formation by FGF signaling.…”

Section: Introductionmentioning

confidence: 99%

FGF signaling activates a Sox9-Sox10 pathway for the formation and branching morphogenesis of mouse ocular glands

et al. 2014

View full text Add to dashboard Cite

Murine lacrimal, harderian and meibomian glands develop from the prospective conjunctival and eyelid epithelia and produce secretions that lubricate and protect the ocular surface. Sox9 expression localizes to the presumptive conjunctival epithelium as early as E11.5 and is detected in the lacrimal and harderian glands as they form. Conditional deletion showed that Sox9 is required for the development of the lacrimal and harderian glands and contributes to the formation of the meibomian glands. Sox9 regulates the expression of Sox10 to promote the formation of secretory acinar lobes in the lacrimal gland. Sox9 and FGF signaling were required for the expression of cartilageassociated extracellular matrix components during early stage lacrimal gland development. Fgfr2 deletion in the ocular surface epithelium reduced Sox9 and eliminated Sox10 expression. Sox9 deletion from the ectoderm did not affect Fgf10 expression in the adjacent mesenchyme or Fgfr2 expression in the epithelium, but appeared to reduce FGF signaling. Sox9 heterozygotes showed a haploinsufficient phenotype, in which the exorbital branch of the lacrimal gland was absent in most cases. However, enhancement of epithelial FGF signaling by expression of a constitutively active FGF receptor only partially rescued the lacrimal gland defects in Sox9 heterozygotes, suggesting a crucial role of Sox9, downstream of FGF signaling, in regulating lacrimal gland branching and differentiation.

show abstract

Conditional disruption of mouse Klf5 results in defective eyelids with malformed meibomian glands, abnormal cornea and loss of conjunctival goblet cells

Cited by 59 publications

References 54 publications

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

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

TGFβ signaling inhibits goblet cell differentiation via SPDEF in conjunctival epithelium

FGF signaling activates a Sox9-Sox10 pathway for the formation and branching morphogenesis of mouse ocular glands

Contact Info

Product

Resources

About