Sprouty2-modulated Kras signaling rescues Shp2 deficiency during lens and lacrimal gland development

Pan, Yi; Carbe, Christian; Powers, Andrea; Feng, Gen‐Sheng; Zhang, Xin

doi:10.1242/dev.042820

Cited by 46 publications

(53 citation statements)

References 37 publications

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“…An increasing number of reports have investigated signaling mechanisms governing branching morphogenesis in the early lacrimal gland (Dean et al, 2004;Makarenkova et al, 2000;Pan et al, 2008Pan et al, , 2010Qu et al, 2011;Voronov et al, 2013). These studies have revealed multiple mechanisms underlying the initial development of the organ.…”

Section: Discussionmentioning

confidence: 99%

Defining epithelial cell dynamics and lineage relationships in the developing lacrimal gland

et al. 2017

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The tear-producing lacrimal gland is a tubular organ that protects and lubricates the ocular surface. The lacrimal gland possesses many features that make it an excellent model in which to investigate tubulogenesis, but the cell types and lineage relationships that drive lacrimal gland formation are unclear. Using single-cell sequencing and other molecular tools, we reveal novel cell identities and epithelial lineage dynamics that underlie lacrimal gland development. We show that the lacrimal gland from its earliest developmental stages is composed of multiple subpopulations of immune, epithelial and mesenchymal cell lineages. The epithelial lineage exhibits the most substantial cellular changes, transitioning through a series of unique transcriptional states to become terminally differentiated acinar, ductal and myoepithelial cells. Furthermore, lineage tracing in postnatal and adult glands provides the first direct evidence of unipotent KRT5 + epithelial cells in the lacrimal gland. Finally, we show conservation of developmental markers between the developing mouse and human lacrimal gland, supporting the use of mice to understand human development. Together, our data reveal crucial features of lacrimal gland development that have broad implications for understanding epithelial organogenesis.

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Section: Discussionmentioning

confidence: 99%

Defining epithelial cell dynamics and lineage relationships in the developing lacrimal gland

et al. 2017

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“…Immunohistochemistry and Histology-Fluorescent immunohistochemistry of cryosections and paraffin sections were performed as described previously (37)(38)(39). The following antibodies were used: mouse anti-Islet1 (1:10), anti-Pax6 (1:10), and anti-Nkx2.2 (1:10) (all from Developmental Studies Hybridoma Bank, Iowa City, IA); mouse anti-Mitf (1:50) (Thermo Scientific, Fremont, CA); rabbit anti-Sox2 (1:800) (Chemicon International, Billerica, MA); rabbit anti-Pax2 (1:100) and rabbit anti-Pax6 (1:250) (both from Covance, Berkeley, CA); rabbit anti-phosphohistone H3 (Ser-10) (1:500) (Upstate, Temecula, CA); and rabbit anti-Ptf1a (1:100) (kindly provided by Dr. Jane E. Johnson, University of Texas Southwestern Medical Center, Dallas, TX).…”

Section: Methodsmentioning

confidence: 99%

“…Secondary antibodies for all experiments were either Alexa Fluor 488-(1:250) or Alexa Fluor 555 (1:500)-conjugated anti-mouse and anti-rabbit IgG (Jackson ImmunoResearch Laboratories, West Grove, PA). For histology of E14.5 paraffin sections of cerebral cortex, hematoxylin and eosin staining was performed as described previously (37).…”

Section: Methodsmentioning

confidence: 99%

“…RNA in Situ Hybridization-RNA in situ hybridization experiments for whole-mount embryos and slide sections were performed as described previously (37)(38)(39). Antisense probes were generated from cDNAs for Crx ( Quantitative Real Time RT-PCR-To compare the expression levels of knock-in Pax6(5a) and Pax2 in embryonic brain at E14.5, they were individually correlated with the endogenous Pax6 expression level in Pax6 5a/ϩ and Pax6 Pax2/ϩ mutants by quantitative real time RT-PCR as described previously (34).…”

Section: Methodsmentioning

confidence: 99%

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An Allelic Series at the Paired Box Gene 6 (Pax6) Locus Reveals the Functional Specificity of Pax Genes

Carbe

Garg

Cai

et al. 2013

Journal of Biological Chemistry

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Background: Pax6, Pax6(5a), and Pax2 are derived from a common Pax2-like ancestral gene. Results: Pax6(5a) and Pax2 can partially substitute for Pax6 in neural development. Conclusion:The specificities of Pax6(5a) and Pax2 paired domains correspond to the extent of the rescues in forebrain but not in eye development. Significance: The unique function of Pax6 in eye development requires the combined activities of paired domain and homeodomain.

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“…Development-Lacrimal gland development is an excellent model for studying the role of heparan sulfate in FGF signaling (29,38,39). Arising from the conjunctival epithelium at the temporal side of the eye, the budding of the lacrimal gland is critically dependent on Fgf10 expressed in the periocular mesenchyme (40,41).…”

Section: Hs2st and Hs6st Are Required For Lacrimal Glandmentioning

confidence: 99%

Lacrimal Gland Development and Fgf10-Fgfr2b Signaling Are Controlled by 2-O- and 6-O-sulfated Heparan Sulfate

Carbe

Tao

et al. 2011

Journal of Biological Chemistry

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Heparan sulfate, an extensively sulfated glycosaminoglycan abundant on cell surface proteoglycans, regulates intercellular signaling through its binding to various growth factors and receptors. In the lacrimal gland, branching morphogenesis depends on the interaction of heparan sulfate with Fgf10-Fgfr2b. To address if lacrimal gland development and FGF signaling depends on 2-O-sulfation of uronic acids and 6-O-sulfation of glucosamine residues, we genetically ablated heparan sulfate 2-O and 6-O sulfotransferases (Hs2st, Hs6st1, and Hs6st2) in developing lacrimal gland. Using a panel of phage display antibodies, we confirmed that these mutations disrupted 2-O and/or 6-O but not N-sulfation of heparan sulfate. The Hs6st mutants exhibited significant lacrimal gland hypoplasia and a strong genetic interaction with Fgf10, demonstrating the importance of heparan sulfate 6-O sulfation in lacrimal gland FGF signaling. Altering Hs2st caused a much less severe phenotype, but the Hs2st;Hs6st double mutants completely abolished lacrimal gland development, suggesting that both 2-O and 6-O sulfation of heparan sulfate contribute to FGF signaling. Combined Hs2st;Hs6st deficiency synergistically disrupted the formation of Fgf10-Fgfr2b-heparan sulfate complex on the cell surface and prevented lacrimal gland induction by Fgf10 in explant cultures. Importantly, the Hs2st;Hs6st double mutants abrogated FGF downstream ERK signaling. Therefore, Fgf10-Fgfr2b signaling during lacrimal gland development is sensitive to the content or arrangement of O-sulfate groups in heparan sulfate. To our knowledge, this is the first study to show that simultaneous deletion of Hs2st and Hs6st exhibits profound FGF signaling defects in mammalian development.Heparan sulfate is a cell-surface glycosaminoglycan playing important roles in the transport and signaling of multiple growth factors, including Hedgehog, Wnt, bone morphogenic protein (BMP), and fibroblast growth factor (FGF) (1-3). Heparan sulfate is first synthesized from the activated monosaccharides, UDP-glucuronic acid and UDP-N-acetylglucosamine, by an Ext copolymerase complex to form a copolymer of glucuronic acid and N-acetylglucosamine. Polymerization is followed by N-deacetylation/N-sulfation of subsets of N-acetylglucosamine residues by N-deacetylase-N-sulfotransferase (Ndst) 2 enzymes (4). Because of the incomplete processing by the Ndst enzymes, the polysaccharide backbone is divided into stretches of variable length of N-sulfated disaccharides (NS domains) and N-acetylated disaccharides (NA domains). A portion of the D-glucuronic acid residues in the NS domains is next converted by glucuronyl C5-epimerase (Hsepi) into l-iduronic acids. A 2-O-sulfotransferase (Hs2st) transfers a sulfate group to the C-2 carbon of the iduronic acids and less frequently to glucuronic acid. Finally, 6-O-sulfotransferases (Hs6st) and more rarely 3-O-sulfotransferases (Hs3st) add sulfate groups to the C-6 and C-3 carbon of the glucosamine residues, respectively. These reactions do not go to completion, lea...

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Sprouty2-modulated Kras signaling rescues Shp2 deficiency during lens and lacrimal gland development

Cited by 46 publications

References 37 publications

Defining epithelial cell dynamics and lineage relationships in the developing lacrimal gland

Defining epithelial cell dynamics and lineage relationships in the developing lacrimal gland

An Allelic Series at the Paired Box Gene 6 (Pax6) Locus Reveals the Functional Specificity of Pax Genes

Lacrimal Gland Development and Fgf10-Fgfr2b Signaling Are Controlled by 2-O- and 6-O-sulfated Heparan Sulfate

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