scholarly journals Single cell multi-omic analysis identifies a Tbx1-dependent multilineage primed population in murine cardiopharyngeal mesoderm

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Hiroko Nomaru ◽  
Yang Liu ◽  
Christopher De Bono ◽  
Dario Righelli ◽  
Andrea Cirino ◽  
...  
Keyword(s):  
Gene Expression ◽  
Single Cell ◽  
22Q11.2 Deletion Syndrome ◽  
Chromatin Accessibility ◽  
Deletion Syndrome ◽  
Congenital Defects ◽  
22Q11.2 Deletion ◽  
T Box ◽  
Pharyngeal Apparatus ◽  
The Face

AbstractThe poles of the heart and branchiomeric muscles of the face and neck are formed from the cardiopharyngeal mesoderm within the pharyngeal apparatus. They are disrupted in patients with 22q11.2 deletion syndrome, due to haploinsufficiency of TBX1, encoding a T-box transcription factor. Here, using single cell RNA-sequencing, we now identify a multilineage primed population within the cardiopharyngeal mesoderm, marked by Tbx1, which has bipotent properties to form cardiac and branchiomeric muscle cells. The multilineage primed cells are localized within the nascent mesoderm of the caudal lateral pharyngeal apparatus and provide a continuous source of cardiopharyngeal mesoderm progenitors. Tbx1 regulates the maturation of multilineage primed progenitor cells to cardiopharyngeal mesoderm derivatives while restricting ectopic non-mesodermal gene expression. We further show that TBX1 confers this balance of gene expression by direct and indirect regulation of enriched genes in multilineage primed progenitors and downstream pathways, partly through altering chromatin accessibility, the perturbation of which can lead to congenital defects in individuals with 22q11.2 deletion syndrome.

scholarly journals Single cell multi-omic analysis identifies a Tbx1-dependent multilineage primed population in the murine cardiopharyngeal mesoderm

2020 ◽  
Author(s):  
Hiroko Nomaru ◽  
Yang Liu ◽  
Christopher De Bono ◽  
Dario Righelli ◽  
Andrea Cirino ◽  
...  
Keyword(s):  
Single Cell ◽  
22Q11.2 Deletion Syndrome ◽  
Chromatin Accessibility ◽  
Deletion Syndrome ◽  
22Q11.2 Deletion ◽  
T Box ◽  
Single Cell Rna Sequencing ◽  
Pharyngeal Apparatus ◽  
The Face ◽  
Continuous Source

AbstractThe poles of the heart and branchiomeric muscles of the face and neck are formed from the cardiopharyngeal mesoderm (CPM) within the pharyngeal apparatus. The formation of the cardiac outflow tract and branchiomeric muscles are disrupted in patients with 22q11.2 deletion syndrome (22q11.2DS), due to haploinsufficiency of TBX1, encoding a T-box transcription factor. Here, using single cell RNA-sequencing, we identified a multilineage primed population (MLP) within the CPM, marked by the Tbx1 lineage, which has bipotent properties to form cardiac and skeletal muscle cells. The MLPs are localized within the nascent mesoderm of the caudal lateral pharyngeal apparatus and provide a continuous source of progenitors that undergo TBX1-dependent progression towards maturation. Tbx1 also regulates the balance between MLP maintenance and maturation while restricting ectopic non-mesodermal gene expression. We further show that TBX1 confers this balance by direct regulation of MLP enriched genes and downstream pathways, partly through altering chromatin accessibility. Our study thus uncovers a new cell population and reveals novel mechanisms by which Tbx1 directs the development of the pharyngeal apparatus, which is profoundly altered in 22q11.2DS.

Differential gene expression in the hippocampus of the Df1/+ mice: A model for 22q11.2 deletion syndrome and schizophrenia

2007 ◽  
Vol 1139 ◽  
pp. 48-59 ◽  
Author(s):  
Sinthuja Sivagnanasundaram ◽  
Danielle Fletcher ◽  
Mike Hubank ◽  
Elizabeth Illingworth ◽  
David Skuse ◽  
...  
Keyword(s):  
Gene Expression ◽  
Differential Gene Expression ◽  
22Q11.2 Deletion Syndrome ◽  
Deletion Syndrome ◽  
22Q11.2 Deletion ◽  
Differential Gene

scholarly journals Mapping morphological malformation to genetic dysfunction in blood vessel organoids with 22q11.2 Deletion Syndrome

2021 ◽  
Author(s):  
Siyu He ◽  
Cong Xu ◽  
Yeh-Hsing Lao ◽  
Shradha Chauhan ◽  
Yang Xiao ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Blood Vessel ◽  
Single Cell ◽  
22Q11.2 Deletion Syndrome ◽  
Vascular Network ◽  
Deletion Syndrome ◽  
22Q11.2 Deletion ◽  
Mural Cells ◽  
Cell Transcriptome ◽  
Single Cell Transcriptome

DiGeorge Syndrome, or 22q11.2 deletion syndrome (22q11.2 DS), is a genetic disorder caused by microdeletions in chromosome 22, impairing the function of endothelial cells (EC) and/or mural cells and leading to deficits in blood vessel development such as abnormal aortic arch morphology, tortuous retinal vessels, and tetralogy of Fallot. The mechanism by which dysfunctional endothelial cells and pericytes contribute to the vasculopathy, however, remains unknown. In this study, we used human blood vessel organoids (VOs) generated from iPSC of 22q11.2 DS patients to model the vascular malformations and genetic dysfunctions. We combined high-resolution lightsheet imaging and single-cell transcriptome analysis to link the genetic profile and vascular phenotype at the single-cell level. We developed a comprehensive analytical methodology by integrating deep learning-mediated blood vessel segmentation, network graph construction, and tessellation analysis for automated morphology characterization. We report that 22q11.2DS VOs demonstrate a smaller size with increased angiogenesis/sprouting, suggesting a less stable vascular network. Overall, clinical presentations of smaller vascular diameter, less connected vasculature, and increased branch points were recapitulated in 22q11.2DS VOs. Single-cell transcriptome profiling showed heterogeneity in both 22q11.2DS and control VOs, but the former demonstrated alterations in endothelial characteristics that are organ-specific and suggest a perturbation in the vascular developmental process. Intercellular communication analysis indicated that the vascular dysfunctions in 22q11.2 deletion were due to a lower cell-cell contact and upregulated extracellular matrix organization involving collagen and fibronectin. Voronoi diagram-based tessellation analysis also indicated that the colocalization of endothelial tubes and mural cells was different between control and 22q11.2 VOs, indicating that alterations in EC and mural interactions might contribute to the deficits in vascular network formation. This study illustrates the utility of VO in revealing the pathogenesis of 22q11.2DS vasculopathy.

scholarly journals Contribution of mitochondrial DNA heteroplasmy to the phenotypic variability in maternally transmitted 22q11.2 deletion syndrome

2020 ◽  
Author(s):  
Boris Rebolledo-Jaramillo ◽  
Maria Gabriela Obregon ◽  
Victoria Huckstadt ◽  
Abel Gomez ◽  
Gabriela M. Repetto
Keyword(s):  
Mitochondrial Dna ◽  
Mitochondrial Function ◽  
22Q11.2 Deletion Syndrome ◽  
Deletion Syndrome ◽  
Congenital Defects ◽  
P Value ◽  
Frequency Change ◽  
22Q11.2 Deletion ◽  
Cardiac Phenotype ◽  
Significant Difference

ABSTRACT22q11.2 deletion syndrome (22q11DS) has an incidence of 1 in 4,000. Most cases occur de novo, but about 10–15% of cases are inherited. Features include congenital heart disease, cleft palate, developmental delay, and other characteristics that can vary even among family members. The presence of nuclear mitochondrial genes in the deleted region, and the requirement of mitochondrial function for proper embryonic development, suggests that intrafamilial variability in maternally transmitted 22q11DS could be explained, at least partially, by variation in mitochondrial DNA (mtDNA). Thus, we sequenced the mtDNA of seventeen 22q11DS mother-child pairs. We identified 29 heteroplasmic variants at the 1% level, and compared the intrafamilial allele frequency change between phenotypically concordant and discordant pairs. We observed a statistically significant difference for the palatal phenotype: p-value = 0.048 (permutation test, 8 concordant vs. 9 discordant pairs), but not for the cardiac phenotype: p-value = 0.568 (6 vs. 11).Mitochondrial function has been primarily studied in mouse models of neurological 22q11DS phenotypes. Our study sets a precedent for considering human mitochondrial variation as a genetic modifier of congenital defects in this syndrome, and although our results are limited by sample size, they suggest a role for mitochondrial variation in the palatal phenotype.

Association of Human Supragranular Enriched Gene Expression With Cortical Thickness Patterns in 22q11.2 Deletion Syndrome

2020 ◽  
Vol 87 (9) ◽  
pp. S366
Author(s):  
Gil Hoftman ◽  
Jennifer Forsyth ◽  
Eva Mennigen ◽  
Amy Lin ◽  
Daqiang Sun ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cortical Thickness ◽  
22Q11.2 Deletion Syndrome ◽  
Deletion Syndrome ◽  
22Q11.2 Deletion

scholarly journals Tbx1 and Foxi3 genetically interact in the third pharyngeal pouch endoderm required for thymus and parathyroid development

2018 ◽  
Author(s):  
Erica Hasten ◽  
Bernice E Morrow
Keyword(s):  
Adherens Junctions ◽  
Mammalian Species ◽  
22Q11.2 Deletion Syndrome ◽  
Deletion Syndrome ◽  
Pharyngeal Pouch ◽  
22Q11.2 Deletion ◽  
The Third ◽  
Transcription Factor Genes ◽  
Pharyngeal Apparatus ◽  
Third Pharyngeal Pouch

SummaryThe mechanisms required for segmentation of the pharyngeal apparatus to individual arches are not precisely delineated in mammalian species. Here, using conditional mutagenesis, we found that two transcription factor genes, Tbx1, the gene for 22q11.2 deletion syndrome and Foxi3, genetically interact in the third pharyngeal pouch endoderm for thymus and parathyroid gland development. We found that Tbx1 is autonomously required for the endoderm to form a temporary multilayered epithelium while invaginating. E-cadherin for adherens junctions remains expressed and cells in the apical boundary express ZO-1. Foxi3 is required autonomously to modulate proliferation and promote later restoration of the endoderm to a monolayer once the epithelia meet after invagination. Completion of this process cooccurs with expression of Alcam needed to stabilize adherens junctions and extracellular, Fibronectin. These processes are required in the third pharyngeal pouch to form the thymus and parathyroid glands, disrupted in 22q11.2 deletion syndrome patients.

Surgical Management of Patients With 22q11.2 Deletion Syndrome

2019 ◽  
Vol 4 (5) ◽  
pp. 857-869
Author(s):  
Oksana A. Jackson ◽  
Alison E. Kaye
Keyword(s):  
Surgical Management ◽  
Preoperative Evaluation ◽  
Preoperative Assessment ◽  
22Q11.2 Deletion Syndrome ◽  
Deletion Syndrome ◽  
22Q11.2 Deletion ◽  
Surgical Decision ◽  
Obstructive Sleep ◽  
Spine Abnormalities ◽  
Speech Assessment

Purpose The purpose of this tutorial was to describe the surgical management of palate-related abnormalities associated with 22q11.2 deletion syndrome. Craniofacial differences in 22q11.2 deletion syndrome may include overt or occult clefting of the palate and/or lip along with oropharyngeal variances that may lead to velopharyngeal dysfunction. This chapter will describe these circumstances, including incidence, diagnosis, and indications for surgical intervention. Speech assessment and imaging of the velopharyngeal system will be discussed as it relates to preoperative evaluation and surgical decision making. Important for patients with 22q11.2 deletion syndrome is appropriate preoperative screening to assess for internal carotid artery positioning, cervical spine abnormalities, and obstructive sleep apnea. Timing of surgery as well as different techniques, common complications, and outcomes will also be discussed. Conclusion Management of velopharyngeal dysfunction in patients with 22q11.2 deletion syndrome is challenging and requires thoughtful preoperative assessment and planning as well as a careful surgical technique.

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