title: Essential functions of the Williams-Beuren syndrome-associated TFII-I genes in embryonic development.
abstract: GTF2I and GTF2IRD1 encoding the multifunctional transcription factors TFII-I and BEN are clustered at the 7q11.23 region hemizygously deleted in Williams-Beuren syndrome (WBS), a complex multisystemic neurodevelopmental disorder. Although the biochemical properties of TFII-I family transcription factors have been studied in depth, little is known about the specialized contributions of these factors in pathways required for proper embryonic development. Here, we show that homozygous loss of either Gtf2ird1 or Gtf2i function results in multiple phenotypic manifestations, including embryonic lethality; brain hemorrhage; and vasculogenic, craniofacial, and neural tube defects in mice. Further analyses suggest that embryonic lethality may be attributable to defects in yolk sac vasculogenesis and angiogenesis. Microarray data indicate that the Gtf2ird1 homozygous phenotype is mainly caused by an impairment of the genes involved in the TGFbetaRII/Alk1/Smad5 signal transduction pathway. The effect of Gtf2i inactivation on this pathway is less prominent, but downregulation of the endothelial growth factor receptor-2 gene, resulting in the deterioration of vascular signaling, most likely exacerbates the severity of the Gtf2i mutant phenotype. A subset of Gtf2ird1 and Gtf2i heterozygotes displayed microcephaly, retarded growth, and skeletal and craniofacial defects, therefore showing that haploinsufficiency of TFII-I proteins causes various developmental anomalies that are often associated with WBS.
authors.affiliation: Department of Reconstructive Sciences, University of Connecticut Health Center, Farmington, CT 06032, USA.
authors.forename: Badam
authors.initials: B
authors.lastname: Enkhmandakh
authors.forename: Aleksandr V
authors.initials: AV
authors.lastname: Makeyev
authors.forename: Lkhamsuren
authors.initials: L
authors.lastname: Erdenechimeg
authors.forename: Frank H
authors.initials: FH
authors.lastname: Ruddle
authors.forename: Nyam-Osor
authors.initials: NO
authors.lastname: Chimge
authors.forename: Maria Isabel
authors.initials: MI
authors.lastname: Tussie-Luna
authors.forename: Ananda L
authors.initials: AL
authors.lastname: Roy
authors.forename: Dashzeveg
authors.initials: D
authors.lastname: Bayarsaihan
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics; D000818:Animals; D047108:Embryonic Development / Q000235:genetics*; D020869:Gene Expression Profiling; D006579:Heterozygote; D051379:Mice; D010641:Phenotype; D015398:Signal Transduction / Q000235:genetics; D019473:Transcription Factors, TFII / Q000235:genetics*; D016212:Transforming Growth Factor beta; D018980:Williams Syndrome / Q000235:genetics*
chemical_list: C486330:Gtf2i protein, mouse; D019473:Transcription Factors, TFII; D016212:Transforming Growth Factor beta