Analysis of the Hand1 cell lineage reveals novel contributions to cardiovascular, neural crest, extra‐embryonic, and lateral mesoderm derivatives

Barnes, Ralston M.; Firulli, Beth A.; Conway, Simon J.; Vincentz, Joshua W.; Firulli, Anthony B.

doi:10.1002/dvdy.22428

Cited by 78 publications

(101 citation statements)

References 33 publications

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“…X-Gal staining of whole-mount and sectioned embryos was performed as described (7,10). All embryo sections are transverse unless otherwise indicated.…”

Section: Methodsmentioning

confidence: 99%

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Exclusion of Dlx5/6 expression from the distal-most mandibular arches enables BMP-mediated specification of the distal cap

Vincentz

Casasnovas

Barnes

et al. 2016

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

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Cranial neural crest cells (crNCCs) migrate from the neural tube to the pharyngeal arches (PAs) of the developing embryo and, subsequently, differentiate into bone and connective tissue to form the mandible. Within the PAs, crNCCs respond to local signaling cues to partition into the proximo-distally oriented subdomains that convey positional information to these developing tissues. Here, we show that the distal-most of these subdomains, the distal cap, is marked by expression of the transcription factor Hand1 (H1) and gives rise to the ectomesenchymal derivatives of the lower incisors. We uncover a H1 enhancer sufficient to drive reporter gene expression within the crNCCs of the distal cap. We show that bone morphogenic protein (BMP) signaling and the transcription factor HAND2 (H2) synergistically regulate H1 distal cap expression. Furthermore, the homeodomain proteins distal-less homeobox 5 (DLX5) and DLX6 reciprocally inhibit BMP/H2-mediated H1 enhancer regulation. These findings provide insights into how multiple signaling pathways direct transcriptional outcomes that pattern the developing jaw.Bmp | DLX | HAND1 | cranial neural crest cells | development A fter migrating to specific locations within the developing embryo, neural crest cells (NCCs), a multipotent cell population originating from the dorsal lip of the neural tube, respond to local morphogenetic signaling cues to pattern and differentiate (1). Following migration to the pharyngeal arches (PAs), cranial NCCs (crNCCs) respond to endothelin 1 (EDN1) and bone morphogenic protein (BMP) signaling from surrounding pharyngeal epithelia to subdivide the PA ectomesenchyme into discrete proximo-distal domains (2). In the mandibular arch (MD1), these nested PA subdomains, characterized by the expression of DLX homeobox and/or HAND basic helix-loop-helix (bHLH) transcription factors, are integral to the development of specific jaw structures, including bone, tongue mesenchyme, and heterogeneous teeth (3). HAND factors regulate mandibular incisor development (4), whereas DLX proteins influence maxillary molar development (2). The mechanisms by which DLX-and HANDdependent transcriptional programs establish proximo-distal PA subdomains are poorly understood. Indeed, the dearth of identified cis-regulatory elements active in postmigratory NCCs has hampered the elucidation of the gene regulatory networks that establish regional identity within the developing mandible.BMP and EDN1 signaling initially overlaps within the distal murine MD1, but by embryonic day (E)10.5, these signaling pathways become spatially segregated. The distal-most tip of the PAs, known as the distal cap, is transiently devoid of active EDN1 signaling. BMP signaling is ostensibly restricted to this distal cap by the localized expression of Bmp antagonists (3). Here, we provide evidence that DLX5 and DLX6 act as transcriptional repressors of BMP signaling specifically within the cranial PAs. We show that, within the crNCCs, the BMP-dependent transcription factors Smads, H2, and GATA2/3 provi...

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“…X-Gal staining of whole-mount and sectioned embryos was performed as described (7,10). All embryo sections are transverse unless otherwise indicated.…”

Section: Methodsmentioning

confidence: 99%

“…Cre knock-in allele provides a tool with which to interrogate cellautonomous roles of Hand factors within the MD1 (7,8). To examine the development of the H1 lineage relative to the developing incisors, we performed X-Gal staining of R26R lacZ/+ ;H1 Cre/+ embryos at E15.5.…”

Section: The H1mentioning

confidence: 99%

Exclusion of Dlx5/6 expression from the distal-most mandibular arches enables BMP-mediated specification of the distal cap

Vincentz

Casasnovas

Barnes

et al. 2016

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

Self Cite

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“…As these CPCs become further specified into each of the cardiovascular cell types, they undergo extensive transcriptional changes associated with their cell type as well as their anatomical position within the developing heart. However, beyond a few well-recognized markers such as Hand1 and Tbx5 for the inflow tract and left ventricle (Barnes et al, 2010; Bruneau et al, 1999); Isl-1 and Sema3c for the outflow tract (Feiner et al, 2001; Sun et al, 2007); Tbx2/3 for the AVC (Christoffels et al, 2004); and Pitx2 for the left atrium (Liu et al, 2002), there are relatively few validated markers that distinguish cells from different regions of the developing heart.…”

Section: Introductionmentioning

confidence: 99%

Transcriptomic Profiling Maps Anatomically Patterned Subpopulations among Single Embryonic Cardiac Cells

et al. 2016

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Summary Embryonic gene expression intricately reflects anatomical context, developmental stage, and cell type. To address whether the precise spatial origins of cardiac cells can be deduced solely from their transcriptional profiles, we established a genome-wide expression database from 118, 949, and 1166 single murine heart cells at embryonic days (e)8.5, 9.5, and 10.5, respectively. We segregated these cells by type using unsupervised bioinformatic analysis and identified chamber-specific genes. Using a random forest algorithm, we reconstructed the spatial origin of single e9.5 and e10.5 cardiomyocytes with 92.0+/-3.2% and 91.2+/-2.8% accuracy respectively (99.4+/-1.0% and 99.1+/-1.1% if a +/-1 zone margin is permitted) and predicted the second heart field distribution of Isl1-lineage descendants. When applied to Nkx2-5-/- cardiomyocytes from murine e9.5 hearts, we showed their transcriptional alteration and lack of ventricular phenotype. Our database and zone classification algorithm will enable the discovery of novel mechanisms in early cardiac development and disease.

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“…First, this protocol provides a common differentiation platform for deriving cardiac and endothelial lineages through simple modulation of activin A and BMP4 concentrations. Second, developmental studies have shown distinct origins and mechanisms for specifying endothelial subtypes such as endocardial, vascular, and lymphatic ECs 20–25 . To this end—using an approach of polarizing hPSC mesoderm at the onset of differentiation—this protocol provides the first approach for controlling EC differentiation from cardiogenic versus hemogenic mesoderm.…”

Section: Introductionmentioning

confidence: 99%

Generating high-purity cardiac and endothelial derivatives from patterned mesoderm using human pluripotent stem cells

et al. 2016

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Human pluripotent stem cells (hpscs) provide a valuable model for the study of human development and a means to generate a scalable source of cells for therapeutic applications. This protocol specifies cell fate efficiently into cardiac and endothelial lineages from hPSCs. The protocol takes 2 weeks to complete and requires experience in hPSC culture and differentiation techniques. Building on lessons taken from early development, this monolayer-directed differentiation protocol uses different concentrations of activin A and bone morphogenetic protein 4 (BMP4) to polarize cells into mesodermal subtypes that reflect mid-primitive-streak cardiogenic mesoderm and posterior-primitive-streak hemogenic mesoderm. this differentiation platform provides a basis for generating distinct cardiovascular progenitor populations that enable the derivation of cardiomyocytes and functionally distinct endothelial cell (EC) subtypes from cardiogenic versus hemogenic mesoderm with high efficiency without cell sorting. ecs derived from cardiogenic and hemogenic mesoderm can be matured into >90% CD31+/VE-cadherin+ definitive ECs. To test the functionality of ECs at different stages of differentiation, we provide methods for assaying the blood-forming potential and de novo lumen-forming activity of ECs. To our knowledge, this is the first protocol that provides a common platform for directed differentiation of cardiomyocytes and endothelial subtypes from hPSCs. This protocol yields endothelial differentiation efficiencies exceeding those of previously published protocols. Derivation of these cell types is a critical step toward understanding the basis of disease and generating cells with therapeutic potential.

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Analysis of the Hand1 cell lineage reveals novel contributions to cardiovascular, neural crest, extra‐embryonic, and lateral mesoderm derivatives

Cited by 78 publications

References 33 publications

Exclusion of Dlx5/6 expression from the distal-most mandibular arches enables BMP-mediated specification of the distal cap

Exclusion of Dlx5/6 expression from the distal-most mandibular arches enables BMP-mediated specification of the distal cap

Transcriptomic Profiling Maps Anatomically Patterned Subpopulations among Single Embryonic Cardiac Cells

Generating high-purity cardiac and endothelial derivatives from patterned mesoderm using human pluripotent stem cells

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