Sox7 in vascular development: review, insights and potential mechanisms.

Cardiovascular development is crucial to the survival of higher organisms, integrally transporting oxygen and nutrients and in later life, facilitating immune function. Only in recent years has the molecular basis of the formation of this ancient conduit system been explored. While transcription factors are essential to specify and differentiate core cellular and structural components of the developing heart and vessels, only a subset of these essential factors are currently known. A transcription factor of emerging importance in the cardiovascular system is Sox7, a member of the F group of Sox genes, as Sox7 removal in recent animal and cellular studies has resulted in disruptions of cardiovascular development. However, the molecular mechanisms of Sox7 action have largely remained obscure. In this paper, we first review the highly conserved and robust cardiovascular expression pattern of Sox7 across multiple species. We then provide evidence of a compelling role for Sox7 in vascular development, elucidating major pathways in which Sox7 functions, including VEGF/Flk1 signaling, Wnt signaling, and Notch pathway. Furthermore, we propose mechanisms connecting all of these important developmental pathways through Sox7, in a way not previously postulated in the developing vascular system. The emerging picture reveals Sox7 as an important developmental gene that connects other vascular regulators and that has significance in human disease.

Mouse model reveals the role of SOX7 in the development of congenital diaphragmatic hernia associated with recurrent deletions of 8p23.1.

Recurrent microdeletions of 8p23.1 that include GATA4 and SOX7 confer a high risk of both congenital diaphragmatic hernia (CDH) and cardiac defects. Although GATA4-deficient mice have both CDH and cardiac defects, no humans with cardiac defects attributed to GATA4 mutations have been reported to have CDH. We were also unable to identify deleterious GATA4 sequence changes in a CDH cohort. This suggested that haploinsufficiency of another 8p23.1 gene may contribute, along with GATA4, to the development of CDH. To determine if haploinsufficiency of SOX7-another transcription factor encoding gene-contributes to the development of CDH, we generated mice with a deletion of the second exon of Sox7. A portion of these Sox7(Δex2/+) mice developed retrosternal diaphragmatic hernias located in the anterior muscular portion of the diaphragm. Anterior CDH is also seen in Gata4(+/-) mice and has been described in association with 8p23.1 deletions in humans. Immunohistochemistry revealed that SOX7 is expressed in the vascular endothelial cells of the developing diaphragm and may be weakly expressed in some diaphragmatic muscle cells. Sox7(Δex2/Δex2) embryos die prior to diaphragm development with dilated pericardial sacs and failure of yolk sac remodeling suggestive of cardiovascular failure. Similar to our experience screening GATA4, no clearly deleterious SOX7 sequence changes were identified in our CDH cohort. We conclude that haploinsufficiency of Sox7 or Gata4 is sufficient to produce anterior CDH in mice and that haploinsufficiency of SOX7 and GATA4 may each contribute to the development of CDH in individuals with 8p23.1 deletions.

Genomic alterations that contribute to the development of isolated and non-isolated congenital diaphragmatic hernia.

BACKGROUND: Congenital diaphragmatic hernia (CDH) is a life threatening birth defect. Most of the genetic factors that contribute to the development of CDH remain unidentified. OBJECTIVE: To identify genomic alterations that contribute to the development of diaphragmatic defects. METHODS: A cohort of 45 unrelated patients with CDH or diaphragmatic eventrations was screened for genomic alterations by array comparative genomic hybridisation or single nucleotide polymorphism based copy number analysis. RESULTS: Genomic alterations that were likely to have contributed to the development of CDH were identified in 8 patients. Inherited deletions of ZFPM2 were identified in 2 patients with isolated diaphragmatic defects and a large de novo 8q deletion overlapping the same gene was found in a patient with non-isolated CDH. A de novo microdeletion of chromosome 1q41q42 and two de novo microdeletions on chromosome 16p11.2 were identified in patients with non-isolated CDH. Duplications of distal 11q and proximal 13q were found in a patient with non-isolated CDH and a de novo single gene deletion of FZD2 was identified in a patient with a partial pentalogy of Cantrell phenotype. CONCLUSIONS: Haploinsufficiency of ZFPM2 can cause dominantly inherited isolated diaphragmatic defects with incomplete penetrance. These data define a new minimal deleted region for CDH on 1q41q42, provide evidence for the existence of CDH related genes on chromosomes 16p11.2, 11q23-24 and 13q12, and suggest a possible role for FZD2 and Wnt signalling in pentalogy of Cantrell phenotypes. These results demonstrate the clinical utility of screening for genomic alterations in individuals with both isolated and non-isolated diaphragmatic defects.