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Vol. 12, Issue 5, 1457-1466, May 2001
3-induced Palatogenesis Requires Matrix Metalloproteinases
§ and
*Division of Hematology-Oncology, Department of Pediatrics;
Cleft lip and palate syndromes are among the most common congenital
malformations in humans. Mammalian palatogenesis is a complex process
involving highly regulated interactions between epithelial and
mesenchymal cells of the palate to permit correct positioning of the
palatal shelves, the remodeling of the extracellular matrix (ECM), and
subsequent fusion of the palatal shelves. Here we show that several
matrix metalloproteinases (MMPs), including a cell membrane-associated
MMP (MT1-MMP) and tissue inhibitor of metalloproteinase-2 (TIMP-2) were
highly expressed by the medial edge epithelium (MEE). MMP-13 was
expressed both in MEE and in adjacent mesenchyme, whereas gelatinase A
(MMP-2) was expressed by mesenchymal cells neighboring the MEE.
Transforming growth factor (TGF)-Department of Biochemistry and Molecular Biology; and
Developmental Biology Program, Department of Pathology,
Childrens Hospital Los Angeles and the Keck School of Medicine of the
University of Southern California, Los Angeles, California 90027
3-deficient mice, which suffer from
clefting of the secondary palate, showed complete absence of TIMP-2 in
the midline and expressed significantly lower levels of MMP-13 and slightly reduced levels of MMP-2. In concordance with these findings, MMP-13 expression was strongly induced by TGF-3 in palatal
fibroblasts. Finally, palatal shelves from prefusion wild-type mouse
embryos cultured in the presence of a synthetic inhibitor of MMPs or
excess of TIMP-2 failed to fuse and MEE cells did not
transdifferentiate, phenocopying the defect of the TGF-3-deficient
mice. Our observations indicate for the first time that the proteolytic
degradation of the ECM by MMPs is a necessary step for palatal fusion.
Current address: MMP Unit, National Institute of
Dental and Craniofacial Research, Bethesda, MD 20892.
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