Foxc1 and Foxc2 and lymphatic sprouting

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Foxc1 and Foxc2 and lymphatic sprouting

Postby patoco » Wed Sep 20, 2006 9:13 pm

The forkhead transcription factors, Foxc1 and Foxc2, are required for arterial specification and lymphatic sprouting during vascular

June 2006

Seo S, Fujita H, Nakano A, Kang M, Duarte A, Kume T.

Division of Cardiovascular Medicine, Department of Medicine, Vanderbilt
University Medical Center, 332 PRB, 2220 Pierce Avenue, Nashville, TN
37232-6300, USA.

Accumulating evidence suggests that in the vertebrate embryo,
acquisition of arterial and venous identity is established early by
genetic mechanisms, including those regulated by vascular endothelial
growth factor (VEGF) and Notch signaling. However, although the
COUP-TFII nuclear receptor has recently been shown to regulate vein
identity, very little is known about the molecular mechanisms of
transcriptional regulation in arterial specification. Here, we show
that mouse embryos compound mutant for Foxc1 and Foxc2, two closely
related Fox transcription factors, exhibit arteriovenous malformations
and lack of induction of arterial markers whereas venous markers such
as COUP-TFII are normally expressed, suggesting that mutant endothelial
cells fail to acquire an arterial fate. Notably, consistent with this
observation, overexpression of Foxc genes in vitro induces expression
of arterial markers such as Notch1 and its ligand Delta-like 4 (Dll4),
and Foxc1 and Foxc2 directly activate the Dll4 promoter via a
Foxc-binding site. Moreover, compound Foxc mutants show a defect in
sprouting of lymphatic endothelial cells from veins in early lymphatic
development, due to reduced expression of VEGF-C. Taken together, our
results demonstrate that Foxc transcription factors are novel
regulators of arterial cell specification upstream of Notch signaling
and lymphatic sprouting during embryonic development.

PMID: 16678147 [PubMed - in process] ... med_docsum


** Update of the FOXC2 gene and insulin regulation:

Foxc2 is a common mediator of insulin and transforming growth factor beta signaling to regulate plasminogen activator inhibitor type I gene expression.

Fujita H, Kang M, Eren M, Gleaves LA, Vaughan DE, Kume T.

Division of Cardiovascular Medicine, Department of Medicine, Vanderbilt
University Medical Center, Nashville, TN 37232-6300, USA.

Elevated plasma levels of plasminogen activator inhibitor type I
(PAI-1), a significant risk factor of ischemic heart disease, are
associated with insulin resistance in which insulin and transforming
growth factor (TGF)-beta play a pivotal role in regulating PAI-1
production. Forkhead transcription factor FOXC2 is an important
regulator of insulin resistance. However, the underlying molecular
mechanisms to link FOXC2 to PAI-1 levels in insulin resistance remain
to be elucidated. Here, we demonstrate that Foxc2 is a common
transcriptional activator of insulin and TGF-beta signaling to directly
regulate PAI-1 expression via 2 distinct target sites, an insulin
response element (IRE) and a novel forkhead-binding element (FBE),
adjacent to a Smad-binding site. We found that in adipocytes and
endothelial cells Foxc2 mediates insulin action competing with another
Forkhead protein, FOXO1, via the insulin response element, and
simultaneously cooperate with the TGF-beta/Smad pathway to
transactivate PAI-1. Importantly, Foxc2 haploinsufficiency in mice
significantly attenuates TGF-beta1-induced PAI-1 expression in the
cardiovascular system and adipose tissue. Taken together, we propose
that Foxc2 is a key molecule to regulate PAI-1 gene expression.

PMID: 16456100 [PubMed - indexed for MEDLINE] ... l/98/5/626


Here is the earlier study done regarding FOXC2 and insulin regulation:

FOXC2 is a winged helix gene that counteracts obesity,
hypertriglyceridemia, and diet-induced insulin resistance.

Cederberg A, Gronning LM, Ahren B, Tasken K, Carlsson P, Enerback S.

Medical Genetics, Department of Medical Biochemistry, Goteborg
University, Box 440, SE-405 30, Goteborg, Sweden.

Obesity, hyperlipidemia, and insulin resistance are common forerunners
of type 2 diabetes mellitus. We have identified the human winged
helix/forkhead transcription factor gene FOXC2 as a key regulator of
adipocyte metabolism. Increased FOXC2 expression, in adipocytes, has a
pleiotropic effect on gene expression, which leads to a lean and
insulin sensitive phenotype. FOXC2 affects adipocyte metabolism by
increasing the sensitivity of the beta-adrenergic-cAMP-protein kinase A
(PKA) signaling pathway through alteration of adipocyte PKA holoenzyme
composition. Increased FOXC2 levels, induced by high fat diet, seem to
counteract most of the symptoms associated with obesity, including
hypertriglyceridemia and diet-induced insulin resistance--a likely
consequence hereof would be protection against type 2 diabetes.

PMID: 11551504 [PubMed - indexed for MEDLINE ... t=Abstract

***** FOXC2 gene mutation is responsible for Lymphedem Praecox-meige which starts at puberty ****


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