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WIREs Dev Biol
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The 22q11 deletion: DiGeorge and velocardiofacial syndromes and the role of TBX1

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Abstract Hemizygous deletion of 22q11 affects approximately 1:4000 live births and may give rise to many different malformations but classically results in a constellation of phenotypes that receive a diagnosis of DiGeorge syndrome or velocardiofacial syndrome. Particularly affected are the heart and great vessels, the endocrine glands of the neck, the face, the soft palate, and cognitive development. Although up to 50 genes may be deleted, it is haploinsufficiency of the transcription factor TBX1 that is thought to make the greatest contribution to the disorder. Mouse embryos are exquisitely sensitive to varying levels of Tbx1 mRNA, and Tbx1 is required in all three germ layers of the embryonic pharyngeal region for normal development. TBX1 controls cell proliferation and affects cellular differentiation in a cell autonomous fashion, but it also directs non‐cell autonomous effects, most notably in the signaling between pharyngeal surface ectoderm and the rostral neural crest. TBX1 interacts with several signaling pathways, including fibroblast growth factor, retinoic acid, CTNNB1 (formerly known as β‐catenin), and bone morphogenetic protein (BMP), and may regulate pathways by both DNA‐binding and non‐binding activity. In addition to the structural abnormalities seen in 22q11 deletion syndrome (DS) and Tbx1 mutant mouse models, patients reaching adolescence and adulthood have a predisposition to psychiatric illness. Whether this has a developmental basis and, if so, which genes are involved is an ongoing strand of research. Thus, knowledge of the genetic and developmental mechanisms underlying 22q11DS has the potential to inform about common disease as well as developmental defect. WIREs Dev Biol 2013, 2:393–403. doi: 10.1002/wdev.75 For further resources related to this article, please visit the WIREs website.

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22q11 deletion syndrome (DS) malformations are secondary to dysmorphogenesis of pharyngeal structures. (a) A schematic lateral view of an embryonic day 10 mouse embryo, showing the relative positions of the pharyngeal arches (PAs), cranial nerves, and otic vesicle. (b) A schematic coronal section of (a) to indicate the organization of the pharyngeal apparatus and tissues with a requirement for Tbx1. Each PA is supplied by a pair of arch arteries, and contains a core of Tbx1‐expressing mesoderm. The pharyngeal endoderm lines the pharyngeal cavity; the location of cells contributing to the glands derived from the endoderm is color coded. Tbx1 is also expressed in the surface ectoderm, where it regulates signals to the ingressing neural crest cells (NCCs) (not shown). OP, otic placode; V–X, fifth to tenth cranial nerves.

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Tbx1 regulatory network in the second heart field (SHF). Tbx1 is negatively regulated by CTNNB1 and miRNA‐17/20a. TBX1 protein binds to, and negatively regulates serum response factor (SRF) and SMAD1. Tbx1 is in epistatsis with Fgf8 and may regulate both FGF8 and FGF10 signaling directly, or via SIX1/EYA1. TBX1 is required for normal expression levels of other transcription factors involved in controlling cellular proliferation and differentiation in the SHF and pharyngeal endoderm. ASH2L co‐activates TBX1‐driven transcription, whereas RIPPLY3 is thought to corepress TBX1 activity. The nature of the various interactions is coded by the lines joining proposed network participants.

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TBX1 regulatory network model: pharyngeal ectoderm and cardiac neural crest. Cardiac neural crest cells (NCCs) are vital for the growth and remodeling of the pharyngeal arch arteries (PAA). Tbx1, Fgf8, and Gbx2 are each required in pharyngeal surface ectoderm for PAA formation. Tbx1 is in epistasis with both Fgf8 and Gbx2 in PAA morphogenesis, but by independent mechanisms. Slit2 expression is diminished in both Tbx1 and Gbx2 ectodermal mutants, and this may make a partial contribution to abnormal neural crest patterning. In addition, lack of Tbx1 expression in the pharyngeal apparatus increases retinoic acid signaling, which is likely to have further deleterious effects on patterning of the neural crest.

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Pharyngeal arch (PA) artery remodeling and defects seen in 22q11 deletion syndrome (DS). (a) A schematic frontal view of the embryonic pharyngeal vessels in different stages of normal development. Arch artery formation has finished by E10.5, resulting in a symmetrical arterial system of paired aortic arches III, IV, VI, and VII intersegmental arteries (ISA). Remodeling has commenced by E11.5, apparent from the narrowing of the carotid ducts. By E12.5 the carotid ducts have regressed completely, the right dorsal aorta is thinner compared with the left counterpart and the aortic sac has septated into a separate ascending aorta (AscAo) and pulmonary trunk. By E13.5 the remodeling process is complete, with the first arterial branch passing to the right as the brachiocephalic artery (BCA), giving rise to the right common carotid (RCC) and right subclavian arteries (RSCA), followed in succession by the left common carotid (LCC) and left subclavian arteries (LSCA). The ductus arteriosus (da) is on the left connecting the proximal left pulmonary artery with the distal aortic arch. (b) A schematic frontal view of the embryonic pharyngeal vessels in different stages of development in the absence of the left fourth arch artery, resulting in an interruption of the aortic arch type‐B (IAA‐B). (c) A schematic frontal view of the embryonic pharyngeal vessels in different stages of development in the absence of the right fourth arch artery, resulting in a cervical origin of the RSCA. III, IV and VI, third, fourth and sixth arch arteries, color coded; VII ISA, seventh intersegmental arteries.

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Birth Defects > Craniofacial and Nervous System Anomalies
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Early Embryonic Development > Development to the Basic Body Plan