transforming-growth-factor-beta and DiGeorge-Syndrome

Growth and remodeling of the pharyngeal arch arteries are vital for the development of a mature great vessel system. Dysmorphogenesis of the fourth arch arteries can result in interruption of the aortic arch type B, typically found in DiGeorge syndrome. Tbx1 haploinsufficient embryos, which model DiGeorge syndrome, display fourth arch artery defects during formation of the vessels. Recovery from such defects is a documented yet unexplained phenotype in Tbx1 haploinsufficiency.. To understand the nature of fourth arch artery growth recovery in Tbx1 haploinsufficiency and its underlying genetic control.. We categorized vessel phenotypes of Tbx1 heterozygotes as hypoplastic or aplastic at the conclusion of pharyngeal artery formation and compared these against the frequency of vessel defects scored at the end of great vessel development. The frequency of hypoplastic vessels decreased during embryogenesis, whereas no reduction of vessel aplasia was seen, implying recovery is attributable to remodeling of hypoplastic vessels. We showed that Smad7, an inhibitory Smad within the transforming growth factor-β pathway, is regulated by Tbx1, is required for arch artery remodeling, and genetically interacts with Tbx1 in this process. Tbx1 and Tbx1;Smad7 haploinsufficiency affected several remodeling processes; however, concurrent haploinsufficiency particularly impacted on the earliest stage of vascular smooth muscle cell vessel coverage and subsequent fibronectin deposition. Conditional reconstitution of Smad7 with a Tbx1Cre driver indicated that the interaction between the 2 genes is cell autonomous.. Tbx1 acts upstream of Smad7 controlling vascular smooth muscle and extracellular matrix investment of the fourth arch artery.

Topics: Animals; Arteries; Binding Sites; Bone Morphogenetic Proteins; Branchial Region; Cell Differentiation; Cell Lineage; Cell Movement; Cell Proliferation; DiGeorge Syndrome; Fibronectins; Gene Expression Regulation, Developmental; Gestational Age; Haploinsufficiency; Heterozygote; Mice; Mice, Inbred C57BL; Mice, Transgenic; Morphogenesis; Muscle, Smooth, Vascular; Phenotype; Regulatory Sequences, Nucleic Acid; Signal Transduction; Smad7 Protein; T-Box Domain Proteins; Transforming Growth Factor beta

Chromosome 22q11.2 deletion syndrome is a common disorder characterized by thymic hypoplasia, conotruncal cardiac defect and hypoparathyroidism. Patients have a risk of infections and autoimmunity associated with T lymphocytopenia. To assess the immunological constitution of patients, the numerical changes and cytokine profile of circulating T cells were analysed by flow cytometry and real-time polymerase chain reaction (PCR). CD3+, CD4+, T cell receptor (TCR)alphabeta+ or CD8alphaalpha+ cell counts were lower, and CD56+ cell counts were higher in patients than in controls during the period from birth to adulthood. The ageing decline of CD3+ or CD4+ cell counts was slower in patients than in controls. The proportion of CD8alphaalpha+ cells increased in controls, and the slope index was larger than in patients. On the other hand, both the number and proportion of Valpha24+ cells increased in patients, and the slope indexes tended to be larger than in controls. The positive correlation of the number of T cells with CD8alphaalpha+ cells was observed only in patients, and that with Valpha24+ cells was seen only in controls. No gene expression levels of interferon (IFN)-gamma, interleukin (IL)-10, transforming growth factor (TGF)-beta, cytotoxic T lymphocyte antigen 4 (CTLA4) or forkhead box p3 (Foxp3) in T cells differed between patients and controls. There was no significant association between the lymphocyte subsets or gene expression levels and clinical phenotype including the types of cardiac disease, hypocalcaemia and frequency of infection. These results indicated that T-lymphocytopenia in 22q11.2 deletion patients became less severe with age under the altered composition of minor subsets. The balanced cytokine profile in the limited T cell pool may represent a T cell homeostasis in thymic deficiency syndrome.

Topics: Adolescent; Adult; Aging; Antigens, CD; Antigens, Differentiation; CD3 Complex; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Child; Child, Preschool; Chromosome Deletion; Chromosomes, Human, Pair 22; CTLA-4 Antigen; Cytokines; DiGeorge Syndrome; Female; Forkhead Transcription Factors; Gene Expression; Humans; Infant; Interferon-gamma; Interleukin-10; Lymphocyte Count; Male; Receptors, Antigen, T-Cell; RNA, Messenger; T-Lymphocytes; Transforming Growth Factor beta

Specific inactivation of TGFbeta signaling in neural crest stem cells (NCSCs) results in cardiovascular defects and thymic, parathyroid, and craniofacial anomalies. All these malformations characterize DiGeorge syndrome, the most common microdeletion syndrome in humans. Consistent with a role of TGFbeta in promoting non-neural lineages in NCSCs, mutant neural crest cells migrate into the pharyngeal apparatus but are unable to acquire non-neural cell fates. Moreover, in neural crest cells, TGFbeta signaling is both sufficient and required for phosphorylation of CrkL, a signal adaptor protein implicated in the development of DiGeorge syndrome. Thus, TGFbeta signal modulation in neural crest differentiation might play a crucial role in the etiology of DiGeorge syndrome.

Topics: Adaptor Proteins, Signal Transducing; Animals; Cell Differentiation; DiGeorge Syndrome; Gene Expression Regulation, Developmental; Humans; Mice; Mice, Knockout; Neural Crest; Nuclear Proteins; Phosphorylation; Signal Transduction; Stem Cells; Transforming Growth Factor beta