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Cleft Palate Craniofac J. 2002 May;39(3):332-40.

Toward pathogenesis of Apert cleft palate: FGF, FGFR, and TGF beta genes are differentially expressed in sequential stages of human palatal shelf fusion.

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1
Craniofacial Centre, Great Ormond Street Hospital for Children, London, England, United Kingdom. j.britto@btinternet.com

Abstract

OBJECTIVE:

Critical cellular events at the palatal medial edge epithelium (MEE) occur in unperturbed mammalian palatogenesis, the molecular control of which involves a number of growth factors including transforming growth factor beta 3 (TGF beta 3). Apert syndrome is a monogenic human disorder in which cleft palate has been significantly correlated to the fibroblast growth factor receptor (FGFR) 2-Ser252Trp mutation. We report the relative expression of these genes in human palatogenesis.

METHODS:

The expression of the IgIIIa/b and IgIIIa/c transcript isoforms of FGFR2 and the proteins FGFR1, FGFR2, and FGFR3 was studied in situ throughout the temporospatial sequence of human palatal shelf fusion and correlated with the expression of TGF beta 3. In addition, the immunolocalization of the ligand FGFs 2, 4, and 7 was undertaken together with the intracellular transcription factor STAT1, which is activated by FGFR signaling.

RESULTS:

FGFRs are differentially expressed in the mesenchyme and epithelia of fusing palatal shelves, in domains overlapping those of their ligands FGF4 and FGF2 but not FGF7. Coexpression is seen with TGF beta 3, which is implicated in MEE dynamics and FGF and FGFR upregulation, and STAT1, an intracellular transcription factor that mediates apoptosis.

CONCLUSIONS:

The coregulation of molecules of the FGFR signaling pathway with TGF beta 3 throughout the stages of human palatal fusion suggests their controlling influence on apoptosis and epitheliomesenchymal transdifferentiation at the MEE. Experimental evidence links FGFR2-IgIIIa/b loss of function with palatal clefting, and these correlated data suggest a unique pathological mechanism for Apert cleft palate.

[Indexed for MEDLINE]

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