Patched1 is required in neural crest cells for the prevention of orofacial clefts

Metzis, Vicki, Courtney, Andrew D., Kerr, Markus C., Ferguson, Charles, Rondón Galeano, Maria C., Parton, Robert G., Wainwright, Brandon J. and Wicking, Carol (2013) Patched1 is required in neural crest cells for the prevention of orofacial clefts. Human Molecular Genetics, Advance Access 24: 1-10. doi:10.1093/hmg/ddt353

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Author Metzis, Vicki
Courtney, Andrew D.
Kerr, Markus C.
Ferguson, Charles
Rondón Galeano, Maria C.
Parton, Robert G.
Wainwright, Brandon J.
Wicking, Carol
Title Patched1 is required in neural crest cells for the prevention of orofacial clefts
Journal name Human Molecular Genetics   Check publisher's open access policy
ISSN 0964-6906
1460-2083
Publication date 2013-07-29
Year available 2013
Sub-type Article (original research)
DOI 10.1093/hmg/ddt353
Open Access Status Not yet assessed
Volume Advance Access
Issue 24
Start page 1
End page 10
Total pages 10
Place of publication Oxford, United Kingdom
Publisher Oxford University Press
Language eng
Abstract Defects such as cleft lip with or without cleft palate (CL/P) are among the most common craniofacial birth defects in humans. In many cases, the underlying molecular and cellular mechanisms that result in these debilitating anomalies remain largely unknown. Perturbed hedgehog (HH) signalling plays a major role in craniofacial development, and mutations in a number of pathway constituents underlie craniofacial disease. In particular, mutations in the gene encoding the major HH receptor and negative regulator, patched1 (PTCH1), are associated with both sporadic and familial forms of clefting, yet relatively little is known about how PTCH1 functions during craniofacial morphogenesis. To address this, we analysed the consequences of conditional loss of Ptch1 in mouse neural crest cell-derived facial mesenchyme. Using scanning electron microscopy (SEM) and live imaging of explanted facial primordia, we captured defective nasal pit invagination and CL in mouse embryos conditionally lacking Ptch1. Our analysis demonstrates interactions between HH and FGF signalling in the development of the upper lip, and reveals cell-autonomous and non-autonomous roles mediated by Ptch1. In particular, we show that deletion of Ptch1 in the facial mesenchyme alters cell morphology, specifically in the invaginating nasal pit epithelium. These findings highlight a critical link between the neural crest cells and olfactory epithelium in directing the morphogenesis of the mammalian lip and nose primordia. Importantly, these interactions are critically dependent on Ptch1 function for the prevention of orofacial clefts.
Formatted abstract
Defects such as cleft lip with or without cleft palate (CL/P) are among the most common craniofacial birth defects in humans. In many cases, the underlying molecular and cellular mechanisms that result in these debilitating anomalies remain largely unknown. Perturbed hedgehog (HH) signalling plays a major role in craniofacial development, and mutations in a number of pathway constituents underlie craniofacial disease. In particular, mutations in the gene encoding the major HH receptor and negative regulator, patched1 (PTCH1), are associated with both sporadic and familial forms of clefting, yet relatively little is known about how PTCH1 functions during craniofacial morphogenesis. To address this, we analysed the consequences of conditional loss of Ptch1 in mouse neural crest cell-derived facial mesenchyme. Using scanning electron microscopy (SEM) and live imaging of explanted facial primordia, we captured defective nasal pit invagination and CL in mouse embryos conditionally lacking Ptch1. Our analysis demonstrates interactions between HH and FGF signalling in the development of the upper lip, and reveals cell-autonomous and non-autonomous roles mediated by Ptch1. In particular, we show that deletion of Ptch1 in the facial mesenchyme alters cell morphology, specifically in the invaginating nasal pit epithelium. These findings highlight a critical link between the neural crest cells and olfactory epithelium in directing the morphogenesis of the mammalian lip and nose primordia. Importantly, these interactions are critically dependent on Ptch1 function for the prevention of orofacial clefts.
Keyword Biochemistry & Molecular Biology
Genetics & Heredity
Biochemistry & Molecular Biology
Genetics & Heredity
BIOCHEMISTRY & MOLECULAR BIOLOGY
GENETICS & HEREDITY
Q-Index Code C1
Q-Index Status Confirmed Code
Grant ID 569713
Institutional Status UQ
Additional Notes Published online 29 July 2013

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2014 Collection
Institute for Molecular Bioscience - Publications
Centre for Microscopy and Microanalysis Publications
 
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Created: Fri, 01 Nov 2013, 01:26:05 EST by Susan Allen on behalf of Institute for Molecular Bioscience