Tbx1 regulates brain vascularization

22q11.2 deletion syndrome (22q11.2DS) is the most common chromosomal microdeletion disorder, estimated to result mainly from de novo non-homologous meiotic recombination events occurring in approximately 1 in every 1,000 fetuses. The first description in the English language of the constellation of findings now known to be due to this chromosomal difference was made in the 1960s in children with DiGeorge syndrome, who presented with the clinical triad of immunodeficiency, hypoparathyroidism and congenital heart disease. The syndrome is now known to have a heterogeneous presentation that includes multiple additional congenital anomalies and later-onset conditions, such as palatal, gastrointestinal and renal abnormalities, autoimmune disease, variable cognitive delays, behavioural phenotypes and psychiatric illness — all far extending the original description of DiGeorge syndrome. Management requires a multidisciplinary approach involving paediatrics, general medicine, surgery, psychiatry, psychology, interventional therapies (physical, occupational, speech, language and behavioural) and genetic counselling. Although common, lack of recognition of the condition and/or lack of familiarity with genetic testing methods, together with the wide variability of clinical presentation, delays diagnosis. Early diagnosis, preferably prenatally or neonatally, could improve outcomes, thus stressing the importance of universal screening. Equally important, 22q11.2DS has become a model for understanding rare and frequent congenital anomalies, medical conditions, psychiatric and developmental disorders, and may provide a platform to better understand these disorders while affording opportunities for translational strategies across the lifespan for both patients with 22q11.2DS and those with these associated features in the general population.

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“…98). Tbx1 has been implicated in brain microvascular development 99 and may play some part in cognitive and behavioural deficits 100 .…”

Section: Mechanisms/pathophysiologymentioning

confidence: 99%

22q11.2 deletion syndrome

McDonald‐McGinn

Sullivan

Marino

et al. 2015

Nat Rev Dis Primers

1,030

1,133

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“…While TBX1 is not expressed in neural crest cells, they are affected by the loss of Tbx1 in ectoderm . Outside of the pharyngeal arches where cells develop into heart, thymus, and parathyroid glands, Tbx1 impacts cell proliferation and brain microvascular development . Cell fate mapping studies have examined the role of Tbx1 in cardiac development and other pharyngeal arch‐derived organs .…”

Section: Genetic Basismentioning

confidence: 99%

Chromosome 22q11.2 deletion syndrome and DiGeorge syndrome

Sullivan

2018

Immunological Reviews

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Summary Chromosome 22q11.2 deletion syndrome is the most common microdeletion syndrome in humans. The effects are protean and highly variable, making a unified approach difficult. Nevertheless, commonalities have been identified and white papers with recommended evaluations and anticipatory guidance have been published. This review will cover the immune system in detail and discuss both the primary features and the secondary features related to thymic hypoplasia. A brief discussion of the other organ system involvement will be provided for context. The immune system, percolating throughout the body can impact the function of other organs through allergy or autoimmune disease affecting organs in deleterious manners. Our work has shown that the primary effect of thymic hypoplasia is to restrict T cell production. Subsequent homeostatic proliferation and perhaps other factors drive a Th2 polarization, most obvious in adulthood. This contributes to atopic risk in this population. Thymic hypoplasia also contributes to low regulatory T cells and this may be part of the overall increased risk of autoimmunity. Collectively, the effects are complex and often age‐dependent. Future goals of improving thymic function or augmenting thymic volume may offer a direct intervention to ameliorate infections, atopy, and autoimmunity.

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“…A first step toward this might be the recent observation that the T-box transcription factor Tbx1 is involved in the vascularization of the brain (Cioffi et al 2013), in a strikingly similar manner to Wnt7a/b (Daneman et al 2009; Stenman et al 2008). Interestingly, Tbx1 is believed to be the major mutated gene in DiGeorge syndrome, a human hereditary disease leading to mental retardation attributable to vascular malformations; Tbx1 has previously been described to be downstream of Wnt/β-catenin in non-endothelial cells (Huh and Ornitz 2010).…”

Section: Development Of the Bbbmentioning

confidence: 99%

Novel insights into the development and maintenance of the blood–brain barrier

2014

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The blood–brain barrier (BBB) is essential for maintaining homeostasis within the central nervous system (CNS) and is a prerequisite for proper neuronal function. The BBB is localized to microvascular endothelial cells that strictly control the passage of metabolites into and out of the CNS. Complex and continuous tight junctions and lack of fenestrae combined with low pinocytotic activity make the BBB endothelium a tight barrier for water soluble moleucles. In combination with its expression of specific enzymes and transport molecules, the BBB endothelium is unique and distinguishable from all other endothelial cells in the body. During embryonic development, the CNS is vascularized by angiogenic sprouting from vascular networks originating outside of the CNS in a precise spatio-temporal manner. The particular barrier characteristics of BBB endothelial cells are induced during CNS angiogenesis by cross-talk with cellular and acellular elements within the developing CNS. In this review, we summarize the currently known cellular and molecular mechanisms mediating brain angiogenesis and introduce more recently discovered CNS-specific pathways (Wnt/β−catenin, Norrin/Frizzled4 and hedgehog) and molecules (GPR124) that are crucial in BBB differentiation and maturation. Finally, based on observations that BBB dysfunction is associated with many human diseases such as multiple sclerosis, stroke and brain tumors, we discuss recent insights into the molecular mechanisms involved in maintaining barrier characteristics in the mature BBB endothelium.

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Tbx1 regulates brain vascularization

Cited by 41 publications

References 29 publications

22q11.2 deletion syndrome

22q11.2 deletion syndrome

Chromosome 22q11.2 deletion syndrome and DiGeorge syndrome

Novel insights into the development and maintenance of the blood–brain barrier

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