Three vertebrate hyaluronan synthases are expressed during mouse development in distinct spatial and temporal patterns

Tien, Janet; Spicer, Andrew P.

doi:10.1002/dvdy.20328

Cited by 85 publications

(74 citation statements)

References 47 publications

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“…In vitro treatment of human periodontal ligament cells with FGF2 resulted in increased heparin sulfate in the supernatant, and may also stimulate HAS1 and HAS2 (37). Has2 is one of three genes encoding HA synthesis and is present during palatogenesis (38). Decreased Has2 expression in the posterior CS palate may have a role in decreased HA accumulation and, interestingly, may also have a role in cellular proliferation as intracellular HA has been suggested as a regulator of proliferation (39).…”

Section: Discussionmentioning

confidence: 99%

Analysis of a gain-of-function FGFR2 Crouzon mutation provides evidence of loss of function activity in the etiology of cleft palate

Snyder‐Warwick¹,

Perlyn

Pan

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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Cleft palate is a common birth defect in humans and is a common phenotype associated with syndromic mutations in fibroblast growth factor receptor 2 (Fgfr2). Cleft palate occurred in nearly all mice homozygous for the Crouzon syndrome mutation C342Y in the mesenchymal splice form of Fgfr2. Mutant embryos showed delayed palate elevation, stage-specific biphasic changes in palate mesenchymal proliferation, and reduced levels of mesenchymal glycosaminoglycans (GAGs). Reduced levels of feedback regulators of FGF signaling suggest that this gain-of-function mutation in FGFR2 ultimately resembles loss of FGF function in palate mesenchyme. Knowledge of how mesenchymal FGF signaling regulates palatal shelf development may ultimately lead to pharmacological approaches to reduce cleft palate incidence in genetically predisposed humans.Crouzon syndrome | fibroblast growth factor receptor 2 | cell proliferation | cell surface receptor | glycosaminoglycan C raniosynostosis syndromes, as well as syndromic and nonsyndromic cleft palate, have been associated with fibroblast growth factor receptor (FGFR) mutations. Of the four highly conserved FGFRs, FGFR2 is the most commonly mutated FGF receptor (1-4). The FGF-FGFR family is involved in multiple intracellular signaling mechanisms in embryonic development, cell growth, wound healing, and tumorigenesis. The FGFRs are receptor tyrosine kinases that signal via a ternary complex of FGFR, FGF, and glycosaminoglycans (GAGs) (5). The ternary complex formation leads to receptor dimerization, autophosphorylation, and activation of downstream signaling cascades (6).FGF-FGFR signaling is active during palatogenesis, and genetic FGF mutations may contribute to 5% of cases of nonsyndromic cleft lip and palate (7). In children with isolated cleft palate, mutations in Fgfr1, Fgfr2, Fgfr3, and Fgf8 have been identified. Additionally, single nucleotide polymorphisms in children with nonsyndromic cleft lip and palate are associated with Fgf3, Fgf7, Fgf10, Fgf18, and Fgfr1, providing confirmation of the importance of the FGF-FGFR system in palate development (7). Knockout mouse models for Fgf10 and Fgfr2b develop cleft palate (8, 9), establishing the necessity of epithelial FGF signaling in normal palatogenesis. Cleft palate in Fgf18 −/− mice (10) suggests that mesenchymal FGF signaling may also be important for palate development.Cleft palate has been associated with both gain-of-function and loss-of-function FGFR mutations (7,(11)(12)(13)(14)(15). Why gain-of-function or loss-of-function mutations result in the same palatal phenotype remains unclear, and understanding this phenomenon may provide additional insight into the pathogenesis of cleft palate. To address this question, we have focused on Crouzon syndrome (CS), a disorder resulting from a missense Fgfr2 mutation that displays an increased incidence of cleft palate in humans (14).CS occurs with an incidence of 12.5 per million births and results from genetic gain-of-function mutations in Fgfr2 (1). Craniofacial anomalies are its hallmark...

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Section: Discussionmentioning

confidence: 99%

Analysis of a gain-of-function FGFR2 Crouzon mutation provides evidence of loss of function activity in the etiology of cleft palate

Snyder‐Warwick¹,

Perlyn

Pan

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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“…The precise biological significance of these diverse catalytic properties of the Has molecules is still not fully understood, nor it is known how the expression and activity of these enzymes may be regulated at the molecular and cellular level. Moreover, the three synthases are expressed in different temporal patterns during mouse development (Tien and Spicer, 2005) and in particular Has2 has been identified as a major source of HA during initial organogenesis. Mice with a homozygous deletion of the Has2 gene manifest severe cardiac and vascular abnormalities leading to death at midgestation (E9.5-10), underpinning a pivotal role of Has2 during mammalian embryogenesis (Camenisch et al, 2000).…”

Section: Introductionmentioning

confidence: 99%

XHas2 activity is required during somitogenesis and precursor cell migration inXenopusdevelopment

et al. 2006

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In vertebrates, hyaluronan biosynthesis is regulated by three transmembrane catalytic enzymes denoted Has1, Has2 and Has3. We have previously cloned the Xenopus orthologues of the corresponding genes and defined their spatiotemporal distribution during development. During mammalian embryogenesis, Has2 activity is known to be crucial, as its abrogation in mice leads to early embryonic lethality. Here, we show that, in Xenopus, morpholino-mediated loss-of-function of XHas2 alters somitogenesis by causing a disruption of the metameric somitic pattern and leads to a defective myogenesis. In the absence of XHas2, early myoblasts underwent apoptosis, failing to complete their muscle differentiation programme. XHas2 activity is also required for migration of hypaxial muscle cells and trunk neural crest cells (NCC). To approach the mechanism whereby loss of HA, following XHas2 knockdown, could influence somitogenesis and precursor cell migration, we cloned the orthologue of the primary HA signalling receptor CD44 and addressed its function through an analogous knockdown approach. Loss of XCD44 did not disturb somitogenesis, but strongly impaired hypaxial muscle precursor cell migration and the subsequent formation of the ventral body wall musculature. In contrast to XHas2, loss of function of XCD44 did not seem to be essential for trunk NCC migration, suggesting that the HA dependence of NCC movement was rather associated with an altered macromolecular composition of the ECM structuring the cells' migratory pathways. The presented results, extend our knowledge on Has2 function and, for the first time, demonstrate a developmental role for CD44 in vertebrates. On the whole, these data underlie and confirm the emerging importance of cell-ECM interactions and modulation during embryonic development.KEY WORDS: Has2, CD44, Hyaluronan, Somitogenesis, Myogenesis, Cell migration, Neural crest, ECM, Xenopus Development 133, 631-640 doi:10.1242/dev.02225 1 Laboratori di Biologia Cellulare e dello Sviluppo, Dipartimento di Fisiologia e Biochimica, Università di Pisa, Via Carducci 13, Ghezzano, Pisa (PI) 56010, Italy. ). These findings have prompted us to investigate the possible role of XHas2 in somitogenesis, myogenic differentiation and trunk NCC migration, which, thus far, have not been possible to elucidate in Has2-null mice. To this end, we have also cloned the Xenopus orthologue of CD44, known to be the principal cell surface receptor of HA (Wheatley et al., 1993;Ponta et al., 2003) for which the precise role during vertebrate development still remains to be elucidated. MATERIALS AND METHODS Embryo manipulations and whole mount in situ hybridizationXenopus laevis embryos obtained by hormone induced laying, were in vitro fertilized, dejelled, washed and incubated in 0.1ϫMMR. Embryos were staged according to Nieuwkoop and Faber (Nieuwkoop and Faber, 1967), fixed and stained for ␤-galactosidase (200-300 pg injected per embryo) as previously described (Sive et al., 2000) using alternatively a red or light-blue substrate for ...

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“…The three members of the Has gene family are located in different chromosomes, expressed at specific stages of organ development (8) and are subject to regulation by different hormonal and environmental signals (9). Although all three HAS isoforms resemble each other in protein sequence and function, some differences have been noted in enzyme stability, chain elongation rate, length of the chain, and substrate-dependent enzyme properties (10 -13).…”

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confidence: 99%

Hyaluronan Synthase 1 (HAS1) Requires Higher Cellular UDP-GlcNAc Concentration than HAS2 and HAS3*

Rilla

Oikari

Jokela

et al. 2013

Journal of Biological Chemistry

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Three vertebrate hyaluronan synthases are expressed during mouse development in distinct spatial and temporal patterns

Cited by 85 publications

References 47 publications

Analysis of a gain-of-function FGFR2 Crouzon mutation provides evidence of loss of function activity in the etiology of cleft palate

Analysis of a gain-of-function FGFR2 Crouzon mutation provides evidence of loss of function activity in the etiology of cleft palate

XHas2 activity is required during somitogenesis and precursor cell migration inXenopusdevelopment

Hyaluronan Synthase 1 (HAS1) Requires Higher Cellular UDP-GlcNAc Concentration than HAS2 and HAS3*

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