Establishment of the Visceral Embryonic Midline Is a Dynamic Process that Requires Bilaterally Symmetric BMP Signaling

Arraf, Alaa A.; Yelin, Ronit; Reshef, Inbar; Kispert, Andreas; Schultheiss, Thomas M.

doi:10.1016/j.devcel.2016.05.018

Cited by 21 publications

(36 citation statements)

References 28 publications

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“…The stages prior to the appearance of aortic hematopoietic clusters are characterized by widespread morphological changes in the AGM region. Our previous studies and those of others have shown that the coelomic epithelium (CE) undergoes Epithelial to Mesenchymal Transition (EMT) to give rise to the sub aortic mesenchyme and dorsal mesentery, and that this subaortic mesenchyme plays an essential role in Runx1 endothelial cell expression and the formation of hematopoietic cells (Arraf et al, 2016;Richard et al, 2013). However, it is not known whether this mesenchyme plays a role in early aortic HE specification.…”

Section: Introductionmentioning

confidence: 99%

Disruption of the aortic wall by coelomic lining-derived mesenchymal cells accompanies the onset of aortic hematopoiesis

Arraf¹,

Bruijn²,

Schultheiss³

2017

Int. J. Dev. Biol.

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In vertebrates, definitive hematopoietic stem cells (HSCs) first emerge in the ventral wall of the aorta in the Aorta-Gonad-Mesonephros (AGM) region of the embryo, where they differentiate from a specialized type of endothelium termed Hemogenic Endothelium (HE). While the transition from HE to hematopoietic tissue has received much experimental attention, much less is known regarding generation of HE itself. The current study investigates the emergence of the HE in the chick embryo aorta. Using the HE marker Runx1 as well as a new chicken-reactive antibody to the endothelial marker VE-Cadherin, we document the relationship between the emerging HE and surrounding tissues, particularly the coelomic epithelium (CE) and CE-derived sub-aortic mesenchyme. In addition, the fate of the CE cells was traced by electroporation of a GFP-expressing plasmid into the CE, followed by analysis using immunofluorescence and in situ hybridization. We make the novel observation that CE-derived mesenchyme transiently invades through the ventral wall of the aorta during the period of establishment of HE and just prior to the emergence of hematopoietic cell clusters in the ventral aortic wall. These observations emphasize a hitherto unappreciated dynamism in the aortic wall during the period of HE generation, and open the door to future studies regarding the role of invasive CE-derived cells during aortic hematopoiesis.

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Section: Introductionmentioning

confidence: 99%

Disruption of the aortic wall by coelomic lining-derived mesenchymal cells accompanies the onset of aortic hematopoiesis

Arraf¹,

Bruijn²,

Schultheiss³

2017

Int. J. Dev. Biol.

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“…Although, in both, looping results from differential growth between the gut tube and mesentery, the degree of differential growth is twofold higher in the chick than the finch (1). Because bone morphogenetic proteins (BMPs) have been strongly implicated in other aspects of gut and mesentery organogenesis (13)(14)(15)(16)(17)(18), we compared BMP signaling in the embryonic chick and finch dorsal mesentery by immunofluorescent detection of phosphorylated Smad 1/5/8. In the chick, phosphoSmad levels temporally correlated with the progression of looping morphogenesis ( Fig.…”

Section: Bmp Signaling Is Enriched In the Looping Chick Dorsal Mesentmentioning

confidence: 99%

BMP signaling controls buckling forces to modulate looping morphogenesis of the gut

Nerurkar

Mahadevan

Tabin

2017

Proc. Natl. Acad. Sci. U.S.A.

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Looping of the initially straight embryonic gut tube is an essential aspect of intestinal morphogenesis, permitting proper placement of the lengthy small intestine within the confines of the body cavity. The formation of intestinal loops is highly stereotyped within a given species and results from differential-growth–driven mechanical buckling of the gut tube as it elongates against the constraint of a thin, elastic membranous tissue, the dorsal mesentery. Although the physics of this process has been studied, the underlying biology has not. Here, we show that BMP signaling plays a critical role in looping morphogenesis of the avian small intestine. We first exploited differences between chicken and zebra finch gut morphology to identify the BMP pathway as a promising candidate to regulate differential growth in the gut. Next, focusing on the developing chick small intestine, we determined that Bmp2 expressed in the dorsal mesentery establishes differential elongation rates between the gut tube and mesentery, thereby regulating the compressive forces that buckle the gut tube into loops. Consequently, the number and tightness of loops in the chick small intestine can be increased or decreased directly by modulation of BMP activity in the small intestine. In addition to providing insight into the molecular mechanisms underlying intestinal development, our findings provide an example of how biochemical signals act on tissue-level mechanics to drive organogenesis, and suggest a possible mechanism by which they can be modulated to achieve distinct morphologies through evolution.

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Section: Discussionmentioning

confidence: 59%

“…The potential of the UCS to act as a switch that may activate or repress depending on cell type is highly relevant in the context of embryogenesis where Bmp2 expression is highly dynamic. A recent study supports the idea that midline positioning of the dorsal mesentery depends on the relative, rather than the actual, amount of BMP signaling on the left and right sides of the developing embryo (Arraf, Yelin, Reshef, Kispert, & Schultheiss, ; Gavrilov and Lacy, ). By potentially up‐regulating BMP2 synthesis in some tissues, but down‐regulating in other tissues, the UCS deletion would disrupt the relative levels of BMP2 in developing tissues and profoundly influence tissue morphogenesis.…”

Section: Discussionmentioning

confidence: 63%

Characterization of new bone morphogenetic protein (Bmp)‐2 regulatory alleles

Shah

Zhu

Shaikh

et al. 2017

Genesis

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Bone morphogenetic protein 2 (BMP2, HGNC:1069, GeneID: 650) is a classical morphogen; a molecule that acts at a distance and whose concentration influences cell proliferation, differentiation, and apoptosis. Key events requiring precise Bmp2 regulation include heart specification and morphogenesis and neural development. In mesenchymal cells, the concentration of BMP2 influences myogenesis, adipogenesis, chondrogenesis, and osteogenesis. Because the amount, timing, and location of BMP2 synthesis influence pattern formation and organogenesis, the mechanisms that regulate Bmp2 are crucial. A sequence within the 3′UTR of the Bmp2 mRNA termed the “ultra-conserved sequence” (UCS) has been largely unchanged since fishes and mammals diverged. Cre-lox mediated deletion of the UCS in a reporter transgene revealed that the UCS may repress Bmp2 in proepicardium, epicardium and epicardium-derived cells (EPDC) and in tissues with known epicardial contributions (coronary vessels and valves). The UCS also repressed the transgene in the aorta, outlet septum, posterior cardiac plexus, cardiac and extra-cardiac nerves and neural ganglia. We used homologous recombination and conditional deletion to generate three new alleles in which the Bmp2 3′UTR was altered as follows: a UCS flanked by loxP sites with or without a neomycin resistance targeting vector, or a deleted UCS. Deletion of the UCS was associated with elevated Bmp2 mRNA and BMP signaling levels, reduced fitness, and embryonic malformations.

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Establishment of the Visceral Embryonic Midline Is a Dynamic Process that Requires Bilaterally Symmetric BMP Signaling

Cited by 21 publications

References 28 publications

Disruption of the aortic wall by coelomic lining-derived mesenchymal cells accompanies the onset of aortic hematopoiesis

Disruption of the aortic wall by coelomic lining-derived mesenchymal cells accompanies the onset of aortic hematopoiesis

BMP signaling controls buckling forces to modulate looping morphogenesis of the gut

Characterization of new bone morphogenetic protein (Bmp)‐2 regulatory alleles

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