BMP signaling restricts hemato-vascular development from lateral mesoderm during somitogenesis

S. Gupta

doi:10.1242/dev.02386

BMP signaling in vascular development and disease

Cytokine & Growth Factor Reviews ◽

10.1016/j.cytogfr.2010.06.001 ◽

2010 ◽

Vol 21 (4) ◽

pp. 287-298 ◽

Cited By ~ 88

Author(s):

Jonathan W. Lowery ◽

Mark P. de Caestecker

Keyword(s):

Vascular Development ◽

Bmp Signaling

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BMP-SMAD1/5 Signaling Regulates Retinal Vascular Development

Biomolecules ◽

10.3390/biom10030488 ◽

2020 ◽

Vol 10 (3) ◽

pp. 488 ◽

Cited By ~ 2

Author(s):

Andreas Benn ◽

Florian Alonso ◽

Jo Mangelschots ◽

Elisabeth Génot ◽

Marleen Lox ◽

...

Keyword(s):

Vascular Development ◽

Bmp Signaling ◽

Loop Formation ◽

Vessel Formation ◽

Sprouting Angiogenesis ◽

Intussusceptive Angiogenesis ◽

Morphogenetic Protein ◽

Vessel Regression ◽

Early Mouse ◽

Tip Cells

Vascular development is an orchestrated process of vessel formation from pre-existing vessels via sprouting and intussusceptive angiogenesis as well as vascular remodeling to generate the mature vasculature. Bone morphogenetic protein (BMP) signaling via intracellular SMAD1 and SMAD5 effectors regulates sprouting angiogenesis in the early mouse embryo, but its role in other processes of vascular development and in other vascular beds remains incompletely understood. Here, we investigate the function of SMAD1/5 during early postnatal retinal vascular development using inducible, endothelium-specific deletion of Smad1 and Smad5. We observe the formation of arterial-venous malformations in areas with high blood flow, and fewer and less functional tip cells at the angiogenic front. The vascular plexus region is remarkably hyperdense and this is associated with reduced vessel regression and aberrant vascular loop formation. Taken together, our results highlight important functions of SMAD1/5 during vessel formation and remodeling in the early postnatal retina.

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Regulation of avian cardiogenesis by Fgf8 signaling

Development ◽

10.1242/dev.129.8.1935 ◽

2002 ◽

Vol 129 (8) ◽

pp. 1935-1943 ◽

Cited By ~ 8

Author(s):

Burak H. Alsan ◽

Thomas M. Schultheiss

Keyword(s):

Ectopic Expression ◽

Early Embryo ◽

Bmp Signaling ◽

Cardiac Markers ◽

Fgf Signaling ◽

Morphogenetic Protein ◽

Low Concentrations ◽

Precardiac Mesoderm ◽

Fgf8 Signaling ◽

Lateral Mesoderm

The avian heart develops from paired primordia located in the anterior lateral mesoderm of the early embryo. Previous studies have found that the endoderm adjacent to the cardiac primordia plays an important role in heart specification. The current study provides evidence that fibroblast growth factor (Fgf) signaling contributes to the heart-inducing properties of the endoderm. Fgf8 is expressed in the endoderm adjacent to the precardiac mesoderm. Removal of endoderm results in a rapid downregulation of a subset of cardiac markers, including Nkx2.5 and Mef2c. Expression of these markers can be rescued by supplying exogenous Fgf8. In addition, application of ectopic Fgf8 results in ectopic expression of cardiac markers. Expression of cardiac markers is expanded only in regions where bone morphogenetic protein (Bmp) signaling is also present, suggesting that cardiogenesis occurs in regions exposed to both Fgf and Bmp signaling. Finally, evidence is presented that Fgf8 expression is regulated by particular levels of Bmp signaling. Application of low concentrations of Bmp2 results in ectopic expression of Fgf8, while application of higher concentrations of Bmp2 result in repression of Fgf8 expression. Together, these data indicate that Fgf signaling cooperates with Bmp signaling to regulate early cardiogenesis.

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New Animal Models Reveal Stage-Specific Hematopoietic Functions for the BMP Signaling Pathway.

Blood ◽

10.1182/blood.v104.11.133.133 ◽

2004 ◽

Vol 104 (11) ◽

pp. 133-133 ◽

Cited By ~ 2

Author(s):

Todd Evans ◽

Sunny Gupta ◽

Lisa M. McReynolds

Keyword(s):

Animal Models ◽

Blood Cell ◽

Signaling Pathway ◽

Hemolytic Anemia ◽

Normal Development ◽

Vascular Development ◽

Bmp Signaling ◽

Dominant Negative ◽

Transgenic Zebrafish ◽

Primitive Erythropoiesis

Abstract Genetic analyses in mouse and zebrafish demonstrate that a conserved BMP signaling pathway is essential for normal development of the embryonic vascular and hematopoietic systems. However, it has not been clear which aspects of hemato-vascular development are regulated by the pathway beyond the initial specification of embryonic mesoderm. We present new animal models for studying BMP signaling at specific stages of both embryonic and adult hematopoiesis. First, we developed approaches to modulate BMP signaling conditionally at specific stages of development in transgenic zebrafish. For this purpose we adapted the Crelox system to express a dominant-negative BMP receptor in cells derived from specific progenitor populations, with subsequent analysis of hematopoietic and vascular development using GFP reporter strains of fish. For example, we find that BMP signaling is required in LMO2+ cells for the normal development of both hematopoietic and vascular systems. Yolk sac vasculature and trunk angiogenesis are both disrupted, and primitive erythropoiesis is also impaired, when these cells express the mutant receptor. In contrast, BMP signaling is apparently no longer required in primitive erythroid cells once they have activated expression of the GATA-1 gene. In a second approach, we studied hematopoiesis in zebrafish mutants for Smad5, which is an intracellular mediator of BMP signaling. For example, homozygote piggytail (pgy) mutant embryos live until day 3–5, yet the fish have little to no blood and no circulation. Surprisingly, we find that key hematopoietic regulatory genes including GATA-1, GATA-2, SCL, and LMO2 are expressed in the pgy mutant fish, but that their patterns of expression are altered. Thus, the progenitor cells initiate a hematopoietic program but fail to differentiate. We also established adult pgy fish that carry a GATA1::GFP transgene, to facilitate the analysis of adult-stage blood cell profiles using flow cytometry. Blood cell populations were monitored under normal conditions and following phenylhydrazine-induced hemolytic anemia in wild-type and pgy/+ fish. Preliminary results indicate that pgy/+ adult fish are able to mount an erythropoietic response to hemolytic anemia. However, the kinetics are altered, specifically in the transition from the proerythroblast to the polychromatophilic erythroblast stage. In summary, we present data using novel animal models disrupted for normal BMP signaling, and demonstrate roles for this pathway at specific stages of differentiation for both embryonic and adult hematopoiesis.

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