A long-deletion mouse model of Williams syndrome reveals Ncf1 -dependent modulation of vascular and neural phenotypes
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Le résumé fourni par la source
Abstract Williams syndrome is a developmental disorder caused by a microdeletion entailing the loss of a single copy of 25-27 genes on chromosome 7q11.23. Patients suffer from cardiovascular and neuropsychological symptoms. Structural abnormalities of the cardiovascular system in Williams syndrome have been attributed to the hemizygous loss of the elastin ( ELN ) gene. In contrast, the neuropsychological consequences of Williams syndrome, including sensorimotor deficits, hypersociability and cognitive impairments, have been mainly attributed to altered expression of transcription factors like LIMK1 , GTF2I and GTF2IRD1 , while the potential impact of altered cerebrovascular function has been largely overlooked. To study the relationship between Williams syndrome mutations and vascularization of both the heart and brain, we generated a mouse model carrying a relatively long microdeletion (LD) that includes the Ncf1 gene, thereby minimizing the confounding impact of hypertension. LD mice had elongated and tortuous aortas but, unlike Eln haploinsufficient mice, showed no signs of structural cardiac hypertrophy. Remarkably, LD mice also displayed structural abnormalities in coronary and brain vessels, including disorganized extracellular matrices. Importantly, LD mice faithfully replicated both cardiovascular and neuropsychological symptoms observed in patients. The phenotype was even more comprehensive than former models, with structure-function correlations evident in aberrant auditory and motor behaviors resembling those in patients with Williams syndrome. Together, our findings suggest that not only cardiovascular but also neuropsychological symptoms in Williams syndrome may be driven in part by vascular abnormalities affecting both heart and brain. Significance Statement Williams syndrome is caused by microdeletion of 25-27 genes on chromosome 7q11.23, resulting in cardiovascular and neuropsychological symptoms. It remains unclear how the affected genes interact and whether cardiovascular deficits influence brain function. We developed and characterized a mouse model with the longest Williams syndrome microdeletion to date. This model reveals interactions between genes that can be compensatory or additive: haploinsufficiency of Ncf1 may counteract the cardiac hypertrophy caused by Eln deletion, while vascular defects that are potentially due to Eln haploinsufficiency extend to the brain and may worsen neuropsychological symptoms. Our findings support the hypothesis that structural vascular deficits putatively contribute to both cardiac and cognitive phenotypes in Williams syndrome, opening new avenues for understanding and treating this syndrome.
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Le contrôle bibliographique ouvert
DOI retrouvé dans Crossref DOI retrouvé, mais le titre doit être comparé manuellement.
- Titre Crossref
- A long-deletion mouse model of Williams syndrome reveals <i>Ncf1</i> -dependent modulation of vascular and neural phenotypes
- Date Crossref
- 31/10/2023
- Éditeur
- openRxiv
- Type
- posted-content
Ce recoupement confirme des métadonnées liées au DOI. Il ne confirme ni la méthode ni les conclusions de l’étude, et il ne compte pas comme une seconde source scientifique indépendante.
Où se fait cette recherche
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Erasmus MC pays non établi dans la noticeÉtablissement de santé
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Erasmus University Rotterdam pays non établi dans la noticeUniversité ou école supérieure
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Center for Excellence in Brain Science and Intelligence Technology pays non établi dans la noticeUniversité ou école supérieure
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Royal Academy of Arts pays non établi dans la noticeOrganisation à but non lucratif
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Royal Netherlands Academy of Arts and Sciences pays non établi dans la noticeOrganisme public
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Netherlands Institute for Neuroscience pays non établi dans la noticeStructure de recherche
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Royal Academy of Art pays non établi dans la noticeUniversité ou école supérieure
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Department of Neuroscience pays non établi dans la noticeInstitution
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Deprtment of Moleculr Genetics pays non établi dans la noticeInstitution
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Department of Molecular Genetics pays non établi dans la noticeInstitution
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Department of Radiology pays non établi dans la noticeInstitution
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Department of Pathology pays non établi dans la noticeInstitution
Erasmus MC, Erasmus University Rotterdam et Center for Excellence in Brain Science and Intelligence Technology, avec 9 autres affiliations.
Une affiliation ne permet pas de déduire la nationalité d’un auteur.