title: Programmed cell death is required for palate shelf fusion and is regulated by retinoic acid.
abstract: The actual role of programmed cell death (PCD) in embryonic processes and the extrinsic signals that define the death fate in developing cells are still poorly understood. Here, we show that during secondary palate shelf fusion in the mouse, PCD appeared in the medial edge epithelia (MEE) of the anterior region only after shelf contact. Contact was necessary for efficient cell death activation in the MEE. However, exogenous all-trans-retinoic acid (RA) increased cell death independently of contact. Competence to induce cell death by contact or by RA exposure was obtained when the MEE were close to touch. Endogenous RA is a relevant regulator of the secondary palate PCD since this was reduced by a retinol dehydrogenase inhibitor and an RAR specific antagonist. Bmp-7 expression was positively regulated by RA. However, BMP-7 was unable to activate cell death within the palate tissue and NOGGIN, a natural BMP antagonist, did not block PCD. Reduction of PCD at the MEE directly with a caspase inhibitor or by inhibiting retinol dehydrogenase resulted in unfused palate shelves, but adhesion was not affected. In contrast, exogenous RA also blocked fusion, but in this situation the increased cell death within the MEE appeared to affect adhesion, thereby causing cleft palate in vivo.
authors.affiliation: Departamento de Genética y Fisiología Molecular, Instituto de Biotecnología, Cuernavaca, Morelos 62210, México.
authors.forename: Rodrigo
authors.initials: R
authors.lastname: Cuervo
authors.forename: Concepción
authors.initials: C
authors.lastname: Valencia
authors.forename: Roshantha A S
authors.initials: RA
authors.lastname: Chandraratna
authors.forename: Luis
authors.initials: L
authors.lastname: Covarrubias
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D055419:Bone Morphogenetic Protein 7; D019485:Bone Morphogenetic Proteins / Q000502:physiology; D002972:Cleft Palate / Q000139:chemically induced; D005260:Female; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D017403:In Situ Hybridization; D051379:Mice; D010159:Palate / Q000187:drug effects* / Q000196:embryology; D011247:Pregnancy; D016212:Transforming Growth Factor beta / Q000235:genetics; D014212:Tretinoin / Q000494:pharmacology*
chemical_list: D055419:Bone Morphogenetic Protein 7; D019485:Bone Morphogenetic Proteins; D016212:Transforming Growth Factor beta; D014212:Tretinoin