Cioffi, Sara (2012) TBX1 IS REQUIRED IN BRAIN VASCULARIZATION. [Tesi di dottorato] (Unpublished)

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Item Type: Tesi di dottorato
Resource language: English
Date: 1 February 2012
Number of Pages: 128
Institution: Università degli Studi di Napoli Federico II
Istituzioni (extra): TIGEM – Telethon Insitute of Genetics and Medicine
Scuola di dottorato: SEMM – European School of Molecular Medicine
Dottorato: PhD in Molecular Medicine (Molecular Oncology or Human Genetics)
Ciclo di dottorato: 23
Coordinatore del Corso di dottorato:
Baldini, AntonioUNSPECIFIED
Simeone, AntonioUNSPECIFIED
Le Noble, FerdinandUNSPECIFIED
Date: 1 February 2012
Number of Pages: 128
Keywords: 22q11.2DS Tbx1 brain angiogenesis
Settori scientifico-disciplinari del MIUR: Area 05 - Scienze biologiche > BIO/11 - Biologia molecolare
Additional information: Ciclo V/XXIII, Curriculum Human Genetics
Date Deposited: 15 Feb 2012 21:00
Last Modified: 12 Jan 2015 13:44

Collection description

The developing microvasculature has a key role in the development, maintenance and repair of the brain and several studies have linked perinatal microvascular damage to an increased risk for schizophrenia and other psychotic disorders. In this work I show for the first time that loss of the transcription factor Tbx1 in mice causes brain vascular abnormalities consisting mainly of a widespread increase in vessel number, vessel perfusion defects and disorganization of the entire brain vessel network. TBX1 is the major gene for 22q11.2 deletion syndrome, which is characterized by cardiovascular, thymic, parathyroid and craniofacial abnormalities. Behavioral disorders are found in most 22q11.2DS patients and an estimated 35-40% of patients develops psychiatric disorders, mainly schizophrenia. Interestingly, mild brain vascular anomalies have been identified in patients by MRI and mainly involve the circle of Willis and the cerebral and vertebral arteries. Mutation of Tbx1 in mice is sufficient to cause most of the clinical features of the syndrome. In mice, Tbx1 is expressed in microvascular endothelial cells (ECs) during mouse brain development. We recently demonstrated that this gene has an essential role in ECs. In particular, EC-specific Tbx1 null mutants died perinatally because of a failure of lymphatic vessel development. Recent genetic studies have provided convincing evidence that haploinsufficiency of Dll4, a vascular-specific Notch ligand is important for embryonic vascular development and arteriogenesis. Dll4 suppresses endothelial tip cell formation and vessel branching by inhibiting the response of sprouting ECs to vascular endothelial growth factor A (Vegf). Consistent with an anti-angiogenic function, mutation of Dll4 in mice causes brain hypervascularization, similar to that seen in the Tbx1 mutant brain. The experimental work presented here indicate that Tbx1 regulates Dll4 in ECs, suggesting that the brain vascular defects identified in Tbx1 mutants may result from decreased expression of Dll4 in ECs and reduced Notch signaling. These data reveal an unexpected role for Tbx1 in brain development.


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