title: Satb2 haploinsufficiency phenocopies 2q32-q33 deletions, whereas loss suggests a fundamental role in the coordination of jaw development.
abstract: The recent identification of SATB2 as a candidate gene responsible for the craniofacial dysmorphologies associated with deletions and translocations at 2q32-q33, one of only three regions of the genome for which haploinsufficiency has been significantly associated with isolated cleft palate, led us to investigate the in vivo functions of murine Satb2. We find that, similar to the way in which SATB2 is perceived to act in humans, craniofacial defects due to haploinsufficiency of Satb2, including cleft palate (in approximately 25% of cases), phenocopy those seen with 2q32-q33 deletions and translocations in humans. Full functional loss of Satb2 results in amplification of these defects and leads both to increased apoptosis in the craniofacial mesenchyme where Satb2 is usually expressed and to changes in the pattern of expression of three genes implicated in the regulation of craniofacial development in humans and mice: Pax9, Alx4, and Msx1. The Satb2-dosage sensitivity in craniofacial development is conspicuous--along with its control of cell survival, pattern of expression, and reversible functional modification by SUMOylation, it suggests that Satb2/SATB2 function in craniofacial development may prove to be more profound than has been anticipated previously. Because jaw development is Satb2-dosage sensitive, the regulators of Satb2 expression and posttranslational modification become of critical importance both ontogenetically and evolutionarily, especially since such regulators plausibly play undetected roles in jaw and palate development and in the etiology of craniofacial malformations.
authors.affiliation: Department of Molecular Biology of Neuronal Signals, Max-Plank Institute for Experimental Medicine, Goettingen, Germany.
authors.forename: Olga
authors.initials: O
authors.lastname: Britanova
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Depew
authors.forename: Manuela
authors.initials: M
authors.lastname: Schwark
authors.forename: Bethan L
authors.initials: BL
authors.lastname: Thomas
authors.forename: Isabelle
authors.initials: I
authors.lastname: Miletich
authors.forename: Paul
authors.initials: P
authors.lastname: Sharpe
authors.forename: Victor
authors.initials: V
authors.lastname: Tarabykin
mesh_terms: D000818:Animals; D017209:Apoptosis; D015139:Blotting, Southern; D002972:Cleft Palate / Q000235:genetics; D019465:Craniofacial Abnormalities / Q000235:genetics; D005091:Exons; D005260:Female; D017353:Gene Deletion; D018628:Gene Dosage; D018507:Gene Expression Regulation, Developmental; D018390:Gene Targeting; D017403:In Situ Hybridization; D007568:Jaw / Q000196:embryology* / Q000502:physiology; D036961:Matrix Attachment Region Binding Proteins / Q000235:genetics* / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008953:Models, Anatomic; D010159:Palate / Q000196:embryology* / Q000502:physiology; D011247:Pregnancy; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014157:Transcription Factors / Q000235:genetics* / Q000502:physiology
chemical_list: D036961:Matrix Attachment Region Binding Proteins; C501473:SATB2 protein, mouse; D014157:Transcription Factors