Histochemical localization of glycosaminoglycans during morphogenesis of the secondary palate in mice

Knudsen, Thomas B.; Bulleit, Robert F.; Zimmerman, Ernest F.

doi:10.1007/bf00707312

Cited by 38 publications

(28 citation statements)

References 23 publications

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“…1,2). This also seems consistent with the fact that there is more hyaluronic acid in the anterior portion of the palate than i n the posterior palate (Knudsen et al, 1985;Brinkley and Morris-Wiman, 1987). Since hyaluronic acid is capable of binding up to ten times its own weight in water and the accumulation of hyaluronic acid results in swelling of the extracellular matrix (Brinkley and Bookstein, 1986), its regional accumulation may play some role in the elevation and remodelling of palatal shelves.…”

Section: Discussionsupporting

confidence: 71%

Expression of the epidermal growth factor receptor in developing fetal mouse palates: An immunohistochemical study

et al. 1990

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Epidermal growth factor (EGF) stimulates the growth of various tissues and, therefore, EGF receptor expression in fetal tissues may play a key role in organogenesis. We have examined immunohistochemically the ontogeny and localization of the EGF receptor in the fetal mouse palate during in vivo and in vitro palatogenesis using the anti-human EGF receptor rabbit antibody. Immunoreactive products against the EGF receptor were observed in the palatal tissue examined on days 12, 13, and 14 of gestation. On days 12 and 13, the immunoreactive products were predominantly positive on the oral and medial edge epithelia but were minimal on the epithelium of the vertical shelf. The EGF receptor immunoreactivity was less intense in the posterior palate as compared with the midpalatal region. In the fusing palate of day 14 fetuses, the cells forming the midline epithelial seam were continuously positive for EGF-R immunoreactivity. The mesenchyme of palatal shelves also showed regional heterogeneity and temporal sequence in EGF receptor expression. The localization of the EGF receptor in fetal mouse palates cultured in a serumless medium generally simulated that observed in vivo.

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Section: Discussionsupporting

confidence: 71%

Expression of the epidermal growth factor receptor in developing fetal mouse palates: An immunohistochemical study

et al. 1990

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“…This finding supports the concept that GAGs are integral to the elevation process. The initial hypothesis that hydration of GAGs produces expansion of the extracellular matrix (ECM), and therefore provides an intrinsic force within the palatal shelf tissue that allows palatal shelf elevation to occur, was postulated by Lazzaro in 1940 (25) and others (26)(27)(28)(29)(30)(31)(32)(33)(34)(35). During palatogenesis, hyaluronic acid and sulfated GAGs are present (26,33).…”

Section: Discussionmentioning

confidence: 99%

“…During palatogenesis, hyaluronic acid and sulfated GAGs are present (26,33). HA is one GAG component and makes up 60-65% of the ECM in the murine palate around the time of palatal shelf reorientation (26,31). Levels of HA are elevated before shelf reorientation, and then decrease once elevation is complete (34,35).…”

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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“…Successful palatal shelf reorientation is prevented by the disruption of HA synthesis both in vivo and in vitro (Wilk et al 1978;Brinkley and Vickerman 1982). The distribution of HA is not random; distinct temporo-spatial patterns of distribution exist which correlate with stages of shelf remodelling (Brinkley and Morris-Wiman 1987;Knudsen et al 1988;Morris-Wiman and Brinkley 1992). Collectively, these observations suggest that HA plays a prominent role in shelf remodelling.…”

Section: Introductionmentioning

confidence: 80%

“…A major component of the extracellular matrix (ECM) of the palatal shelf during its remodelling is hyaluronate (HA) (Pratt et al 1973;Brinkley and Morris-Wiman 1987;Knudsen et al 1988;Morris-Wiman and Brinkley 1992). HA-rich extracellular matrices have been associated with the increased hydration of tissues and are believed to play a major role in the rapid expansion of intercellular spaces that occurs in other developing systems during cell migration or changes in tissue architecture (for review, see Toole 1981).…”

Section: Introductionmentioning

confidence: 99%

Rapid changes in the extracellular matrix accompany in vitro palatal shelf remodelling

Morris-Wiman

Brinkley

1993

Anat Embryol

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The sequence of events and the distribution of extracellular matrix (ECM) components was examined during mouse secondary palatal shelf elevation in an in vitro model using standard roller tube culture methods developed for the culture of early embryos. In this culture system, the morphological changes associated with remodelling and reorientation of the palatal shelves of gestational day 13 mouse fetuses were similar to those observed in vivo. However, in specimens explanted 24-30 h prior to reorientation in vivo, remodelling began rapidly after explantation, and significant reorientation was accomplished within 4 h. Midline contact between the shelves did not occur until after 18 h in vitro, concomitant with shelf growth. Therefore, in this in vitro model, events related to palatal shelf remodelling and reorientation can be distinguished from those related to shelf growth. We used this in vitro model to characterize the transient changes in ECM distribution and accumulation that occur concomitant with events in shelf remodelling. Our results show that, during rapid remodelling in vitro, the relative distributions of collagen III, fibronectin and hyaluronate, as visualized by immunofluorescent staining, decreased within specific regions of the mesenchymal compartment. In contrast, the distribution of collagen I within the mesenchyme increased, and the distribution of tenascin did not change significantly. All molecules examined, except tenascin, showed changes in distribution within the basement membrane. These patterns of distribution are similar to those observed during more gradual remodelling in vivo. During remodelling in vitro, the deposition of [3H]-glucosamine- and [3H]-proline-labelled components of the ECM, as visualized by autoradiography, was greatest during the first 3 h of culture. During this period, labelled ECM accumulated within specific regions of the mesenchyme and palatal epithelial basement membrane. Uptake was reduced dramatically during the subsequent 3 h in culture and was restricted mainly to the palatal epithelium and its underlying basement membrane. The in vitro system permitted the characterization of early events in shelf remodelling leading to reorientation. Results suggest that remodelling is accompanied by rapid, local accumulation of ECM in specific regions of the palatal shelf previously thought to play a role in the process.

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Histochemical localization of glycosaminoglycans during morphogenesis of the secondary palate in mice

Cited by 38 publications

References 23 publications

Expression of the epidermal growth factor receptor in developing fetal mouse palates: An immunohistochemical study

Expression of the epidermal growth factor receptor in developing fetal mouse palates: An immunohistochemical study

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

Rapid changes in the extracellular matrix accompany in vitro palatal shelf remodelling

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