Glycosaminoglycan-dependent restriction of FGF diffusion is necessary for lacrimal gland development

Qu, Xiuxia; Pan, Yi; Carbe, Christian; Powers, Andrea; Grobe, Kay; Zhang, Xin

doi:10.1242/dev.079236

Cited by 48 publications

(56 citation statements)

References 45 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Heparan sulfate is required for the interaction of FGFs with FGF receptors (Qu et al, 2012). Heparan sulfate (glucosamine) 3-O-sulfotransferase 3B1 (Hs3st3b1) and 3A1 (Hs3st3a1) mRNA were strongly expressed in lacrimal bud tip cells (Fig.…”

Section: Sox9-regulated Transcripts Appear To Be Co-regulated By Fgf mentioning

confidence: 99%

“…ERK phosphorylation is one measure of FGF receptor activation. Activation of the MAP kinase pathway increases levels of the transcription factor Etv5, which promotes the expression of the dualspecificity phosphatase Dusp6, a feedback inhibitor of the MAP kinase pathway (Qu et al, 2012). Spry2 is also a feedback inhibitor expressed in response to FGF signaling (Pan et al, 2010).…”

Section: Sox9-regulated Transcripts Appear To Be Co-regulated By Fgf mentioning

confidence: 99%

“…Lacrimal and harderian gland development begins on embryonic day (E) 13.5 and 15.5, respectively, when Fgf10 in the periocular mesenchyme interacts with fibroblast growth factor receptor 2b (Fgfr2b) in the ectoderm to induce bud outgrowth Makarenkova et al, 2000;Tsau et al, 2011;Qu et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

“…Negatively charged GAGs control the FGF-FGFR interaction to activate downstream signaling, limit the diffusion of Fgf10 and stabilize the FGFs in the mesenchyme (Qu et al, 2012). Inactivation of heparan sulfate biosynthesis enzymes in the prospective lacrimal gland epithelium prevents the formation of lacrimal glands; the lacrimal gland was either severely reduced in size or missing in Ndst1 mutants and lost altogether in Ndst1/2 double mutants (Pan et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

“…Hs2st; Hs6st double mutants also lacked lacrimal gland development (Qu et al, 2011). In Ugdh mutants, loss of GAGs resulted in excessive Fgf10 diffusion, which inhibited lacrimal gland budding (Qu et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

See 4 more Smart Citations

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

Section: Sox9-regulated Transcripts Appear To Be Co-regulated By Fgf mentioning

confidence: 99%

Section: Sox9-regulated Transcripts Appear To Be Co-regulated By Fgf mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

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

show abstract

Role of heparan sulfate proteoglycans in optic disc and stalk morphogenesis

Cai

Grobe

Zhang

2014

Developmental Dynamics

Self Cite

View full text Add to dashboard Cite

Background Heparan sulfate proteoglycans (HSPG) are important for embryonic development via the regulation of gradient formation and signaling of multiple growth factors and morphogens. Previous studies have shown that Bmp/Shh/Fgf signaling are required for the regionalization of the optic vesicle (OV) and for the closure of the optic fissure (OF), the disturbance of which underlie ocular anomalies such as microphthalmia, coloboma and optic nerve hypoplasia. Results To study HSPG-dependent coordination of these signaling pathways during mammalian visual system development, we have generated a series of OV-specific mutations in the heparan sulfate (HS) N-sulfotransferase genes (Ndst1 and Ndst2) and HS O-sulfotransferase genes (Hs2st, Hs6st1 and Hs6st2) in mice. Interestingly, the resulting HS undersulfation still allowed for normal retinal neurogenesis and optic fissure closure, but led to defective optic disc and stalk development. The adult mutant animals further developed optic nerve aplasia/hypoplasia and displayed retinal degeneration. We observed that MAPK/ERK signaling was down-regulated in Ndst mutants, and consistent with this, HS-related optic nerve morphogenesis defects in mutant mice could partially be rescued by constitutive Kras activation. Conclusions These results suggest that HSPGs, depending on their HS sulfation pattern, regulate multiple signaling pathways in optic disc and stalk morphogenesis.

show abstract

Lacrimal gland development: From signaling interactions to regenerative medicine

Garg

Zhang

2017

Developmental Dynamics

Self Cite

View full text Add to dashboard Cite

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.

show abstract

Glycosaminoglycan-dependent restriction of FGF diffusion is necessary for lacrimal gland development

Cited by 48 publications

References 45 publications

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

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

Role of heparan sulfate proteoglycans in optic disc and stalk morphogenesis

Lacrimal gland development: From signaling interactions to regenerative medicine

Contact Info

Product

Resources

About