Biomedical subjects

Jelena S Arnold

Publications and source records attributed to Jelena S Arnold.

4 recordsLinked to original sources

PubMed2006

T-genes and limb bud development.

The T-box family of transcriptional factors is ancient and highly conserved among most species of animals. Haploinsufficiency of multiple T-box proteins results in severe human congenital malformation syndromes, involving craniofacial, cardiovascular, and skeletal structures. These genes have major roles in embryogenesis, including the development of the limbs. Formation of the limbs begins with a limb bud and its morphogenesis requires complex epithelial-mesenchymal interactions. Recent studies have shown that T, Tbx2, Tbx3, Tbx4, Tbx5, Tbx15, and Tbx18 are all expressed in the limb buds, and many have developmental functions. The study of these genes is clinically relevant as mutations in several of them cause human congenital malformation syndromes. Furthermore, understanding the function and biology of these genes is important in understanding normal embryogenesis.

Gene Expression Regulation, Developmental↗

PubMed2006

Tissue-specific roles of Tbx1 in the development of the outer, middle and inner ear, defective in 22q11DS patients.

Most 22q11.2 deletion syndrome (22q11DS) patients have middle and outer ear anomalies, whereas some have inner ear malformations. Tbx1, a gene hemizygously deleted in 22q11DS patients and required for ear development, is expressed in multiple tissues during embryogenesis. To determine the role of Tbx1 in the first pharyngeal pouch (PPI) in forming outer and middle ears, we tissue-specifically inactivated the gene using Foxg1-Cre. In the conditional mutants, PPI failed to outgrow, preventing the middle ear bone condensations from forming. Tbx1 was also inactivated in the otic vesicle (OV), resulting in the failure of inner ear sensory organ formation, and in duplication of the cochleovestibular ganglion (CVG). Consistent with the anatomical defects, the sensory genes, Otx1 and Bmp4 were downregulated, whereas the CVG genes, Fgf3 and NeuroD, were upregulated. To delineate Tbx1 cell-autonomous roles, a more selective ablation, exclusively in the OV, was performed using Pax2-Cre. In contrast to the Foxg1-Cre mutants, Pax2-Cre conditional mutant mice survived to adulthood and had normal outer and middle ears but had the same inner ear defects as the Tbx1 null mice, with the same gene expression changes. These results demonstrate that Tbx1 has non-cell autonomous roles in PPI in the formation of outer and middle ears and cell-autonomous roles in the OV. Periotic mesenchymal markers, Prx2 and Brn4 were normal in both conditional mutants, whereas they were diminished in Tbx1-/- embryos. Thus, Tbx1 in the surrounding mesenchyme in both sets of conditional mutants cannot suppress the defects in the OV that occur in the null mutants.

Animals↗

PubMed2006

Inactivation of Tbx1 in the pharyngeal endoderm results in 22q11DS malformations.

The 22q11 deletion (22q11DS; velo-cardio-facial syndrome/DiGeorge syndrome) is characterized by defects in the derivatives of the pharyngeal apparatus. Mouse genetic studies have identified Tbx1, a member of the T-box family of transcription factors, as being responsible for the physical malformations of the syndrome. Mice heterozygous for a null mutation in Tbx1 have mild anomalies, whereas homozygous Tbx1 mutants die at birth with severe defects in the derivatives of the pharyngeal apparatus, including cleft palate, thymus gland aplasia and cardiac outflow tract malformations. Tbx1 is expressed in the splanchnic mesenchyme, the pharyngeal endoderm (PE) and in the core mesoderm of the pharyngeal apparatus. Tissue interactions between the epithelia and mesenchyme of the arches are required for development of the pharyngeal apparatus; the precise role of Tbx1 in each tissue is not known. To assess the role of Tbx1 in the PE, a conditional allele of Tbx1 was generated using the Cre/loxP system. Foxg1-Cre was used to drive PE-specific ablation of Tbx1. Conditional null mutants survived embryogenesis, but died in the neonatal period with malformations identical to the defects observed in Tbx1 homozygous null mutants. The abnormalities appear to be secondary to failed outgrowth of the pharyngeal pouches. These results show that Tbx1 in the PE is required for the patterning and development of the pharyngeal apparatus, thereby disrupting the formation of its derivative structures.

Animals↗

PubMed2004

Full spectrum of malformations in velo-cardio-facial syndrome/DiGeorge syndrome mouse models by altering Tbx1 dosage.

Velo-cardio-facial syndrome/DiGeorge syndrome (VCFS/DGS) is associated with de novo hemizygous 22q11.2 deletions and is characterized by malformations attributed to abnormal development of the pharyngeal arches and pouches. The main physical findings include aortic arch and outflow tract heart defects, thymus gland hypoplasia or aplasia and craniofacial anomalies. The disorder varies greatly in expressivity; while some patients are mildly affected with learning disabilities and subtle craniofacial malformations, others die soon after birth with major cardiovascular defects and thymus gland aplasia. In addition to the main clinical features, many other findings are associated with the disorder such as chronic otitis media and hypocalcemia. Tbx1, a gene encoding a T-box transcription factor, which is hemizygously deleted on chromosome 22q11.2, was found to be a strong candidate for the equivalent of human VCFS/DGS in mice. Mice hemizygous for a null allele of Tbx1 had mild malformations, while homozygotes had severe malformations in the affected structures; neither precisely modeling the syndrome. Interestingly, bacterial artificial chromosome (BAC) transgenic mice overexpressing human TBX1 and three other transgenes, had similar malformations as VCFS/DGS patients. By employing genetic complementation studies, we demonstrate that altered TBX1 dosage and not overexpression of the other transgenes is responsible for most of the defects in the BAC transgenic mice. Furthermore, the full spectrum of VCFS/DGS malformations was elicited in a Tbx1 dose dependent manner, thus providing a molecular basis for the pathogenesis and varied expressivity of the syndrome.

Animals↗