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.

The “soft” side of the bone: unveiling its endocrine functions

“…Experiments performed with Satb2 knock-out (KO) mice as well as haploinsufficiency of SATB2 in humans revealed the involvement of this transcription factor in craniofacial pattern and osteoblast differentiation [26,27]. It physically interacts with both Runx2 and ATF4, eventually leading to a positive regulation of osteoblast markers [28].…”

Application of Immunohistochemistry in Gastrointestinal and Liver Neoplasms: New Markers and Evolving Practice

“…[69][70][71][72] Studies have shown that SATB2 carries out a wide spectrum of biologic functions. It is a transcriptional activator of immunoglobulin l expression.…”

X chromosome inactivation: A silence that needs to be broken

“…SATB1 does not colocalize with Xist RNA in ES cells. Single gene disruption of either SATB1 or SATB2 was compatible with female development (Alvarez et al, 2000;Britanova et al, 2006;Dobreva et al, 2006). Data of double gene disruption of SATB1 and SATB2 are currently not available.…”