Hand2 Inhibits Kidney Specification While Promoting Vein Formation Within the Posterior Mesoderm

Perens, Elliot A.; Garavito‐Aguilar, Zayra V.; Guio-Vega, Gina P.; Peña, Karen T; Schindler, Yocheved L.; Yelon, Deborah

doi:10.1101/075036

Cited by 7 publications

(33 citation statements)

References 61 publications

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“…3F). Extending previous observations (Gays et al, 2017;Mao et al, 2015;Perens et al, 2016;Yin et al, 2010), these data suggest that hand2:EGFP reporter expression at 3 dpf in zebrafish delineates the visceral and parietal peritoneal membranes.…”

Section: Hand2 Expression Identifies Mesothelial Progenitorssupporting

confidence: 88%

Hand2 delineates mesothelium progenitors and is reactivated in mesothelioma

Crowell

Nieuwenhuize

et al. 2020

Preprint

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The mesothelium forms epithelial membranes that line the bodies cavities and surround the internal organs. Mesothelia widely contribute to organ homeostasis and regeneration, and their dysregulation can result in congenital anomalies of the viscera, ventral wall defects, and mesothelioma tumors. Nonetheless, the embryonic ontogeny and developmental regulation of mesothelium formation has remained uncharted. Here, we combine genetic lineage tracing, in toto live imaging, and single-cell transcriptomics in zebrafish to track mesothelial progenitor origins from the lateral plate mesoderm (LPM). Our single-cell analysis uncovers a post-gastrulation gene expression signature centered on hand2 that delineates distinct progenitor populations within the forming LPM. Combining gene expression analysis and imaging of transgenic reporter zebrafish embryos, we chart the origin of mesothelial progenitors to the lateral-most, hand2-expressing LPM and confirm evolutionary conservation in mouse. Our time-lapse imaging of transgenic hand2 reporter embryos captures zebrafish mesothelium formation, documenting the coordinated cell movements that form pericardium and visceral and parietal peritoneum. We establish that the primordial germ cells migrate associated with the forming mesothelium as ventral migration boundary. Functionally, hand2 mutants fail to close the ventral mesothelium due to perturbed migration of mesothelium progenitors. Analyzing mouse and human mesothelioma tumors hypothesized to emerge from transformed mesothelium, we find de novo expression of LPM-associated transcription factors, and in particular of Hand2, indicating the re-initiation of a developmental transcriptional program in mesothelioma. Taken together, our work outlines a genetic and developmental signature of mesothelial origins centered around Hand2, contributing to our understanding of mesothelial pathologies and mesothelioma.

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Section: Hand2 Expression Identifies Mesothelial Progenitorssupporting

confidence: 88%

Hand2 delineates mesothelium progenitors and is reactivated in mesothelioma

Crowell

Nieuwenhuize

et al. 2020

Preprint

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“…The strong proximal deficiencies observed in osr1 mutants were reminiscent of the pronephron phenotypes previously shown to result from overexpression of hand2 (Perens et al, 2016).…”

Section: Mutation Of Osr1 Has Graded Effects Along the Proximal-distasupporting

confidence: 55%

“…Previously we found that hand2 constrains the size of the pronephron by repressing IM formation (Perens et al, 2016). Considering the genetic interaction between hand2 and osr1 during pronephron development, we investigated whether osr1 also regulates the extent of initial IM formation.…”

Section: Osr1 Is Required To Generate the Full Complement Of Intermedmentioning

confidence: 97%

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osr1couples intermediate mesoderm cell fate with temporal dynamics of vessel progenitor cell differentiation

Perens

Diaz

Quesnel

et al. 2020

Preprint

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Transcriptional regulatory networks refine gene expression boundaries throughout embryonic development to define the precise dimensions of organ progenitor territories. Kidney progenitors originate within the intermediate mesoderm (IM), but the pathways that establish the boundary between the IM and its neighboring vessel progenitors are poorly understood. Here, we delineate new roles for the zinc finger transcription factor Osr1 in kidney and vessel progenitor development. Zebrafish osr1 mutants display decreased IM formation and premature emergence of neighboring lateral vessel progenitors (LVPs). These phenotypes contrast with the increased IM and absent LVPs observed with loss of the bHLH transcription factor Hand2, and loss of hand2 partially suppresses the osr1 mutant phenotypes. hand2 and osr1 are both expressed in the posterior lateral mesoderm, but osr1 expression decreases dramatically prior to LVP emergence. Overexpressing osr1 inhibits LVP development while enhancing IM formation. Together, our data demonstrate that osr1 modulates both the extent of IM formation and the temporal dynamics of LVP development, suggesting that a balance between levels of osr1 and hand2 expression is essential to demarcate the dimensions of kidney and vessel progenitor territories.SUMMARY STATEMENTAnalysis of the osr1 mutant phenotype reveals roles in determining the extent of intermediate mesoderm formation while inhibiting premature differentiation of neighboring vessel progenitors.

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“…We find that while pax2.1:EGFP in early somitogenesis marks midbrain-hindbrain precursor cells of ectodermal origin, the likewise pax2.1:EGFP-expressing PLPM-derived pronephric epithelial precursors (Picker et al, 2002) also express drl:mCherry ( Fig 1K). Moreover, hand2:EGFP expression, which demarcates the lateral-most PLPM domain plus parts of the ALPM-derived heart field and pectoral fin precursors (Perens et al, 2016;Yelon et al, 2000), was also fully situated within the pan-LPM expression domain of drl:mCherry ( Fig 1L). Taken together, these data provide a continuous view of the emerging LPM stripes from gastrulation in zebrafish and document that the LPM emerges around the entire circumference of the zebrafish embryo ( Fig 1M).…”

Section: The Lpm Emerges As a Dedicated Mesendoderm Populationmentioning

confidence: 92%

A conserved regulatory program drives emergence of the lateral plate mesoderm

Hess

Nieuwenhuize

et al. 2018

Preprint

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Abstract:Cardiovascular cell lineages emerge with kidney, smooth muscle, and limb skeleton progenitors from the lateral plate mesoderm (LPM). How the LPM emerges during development and how it has evolved to form key lineages of the vertebrate body plan remain unknown. Here, we captured LPM formation by transgenic in toto imaging and lineage tracing using the first pan-LPM enhancer element from the zebrafish gene draculin (drl). drl LPM enhancer-based reporters are specifically active in LPM-corresponding territories of several chordate species, uncovering a universal LPM-specific gene program. Distinct from other mesoderm, we identified EomesA, FoxH1, and MixL1 with BMP/Nodal-controlled Smad activity as minimally required factors to drive drl-marked LPM formation. Altogether, our work provides a developmental and mechanistic framework for LPM emergence and the in vitro differentiation of cardiovascular cell types. Our findings suggest that the LPM may represent an ancient cell fate domain that predates ancestral vertebrates.. CC-BY-NC-ND 4.0 International license peer-reviewed) is the author/funder. It is made available under aThe copyright holder for this preprint (which was not . http://dx.doi.org/10.1101/261115 doi: bioRxiv preprint first posted online Feb. 7, 2018; 2 Main Text:Following gastrulation, mesoderm in vertebrates is classically described to partition into axial, paraxial, and lateral domains (Gurdon, 1995). The ventrally forming lateral plate mesoderm (LPM) is composed of highly mobile cells and is mainly defined by its position adjacent to the somite-forming paraxial mesoderm (Hatada and Stern, 1994). Transplantation and lineage tracing experiments in several species have shown that the LPM contains progenitor cells of the circulatory system, smooth muscle lineages, the kidneys (often demarcated as dedicated intermediate mesoderm), and the limb anlagen (Chal and Pourquié, 2017; Gurdon, 1995; Takasato and Little, 2015). Several transcription factors including Hand1/2, Tbx5, Osr1, FoxF1, Prrx1, Mesp1, and Etv2 are expressed in LPM territories and play overlapping roles in cell fate determination (Chal and Pourquié, 2017;Davidson and Zon, 2004; Takasato and Little, 2015), albeit not always with conserved function (Yabe et al., 2016). Anterior-to-posterior expression domains of select transcription factors including Tbx1/10 and Hand are conserved in lampreys and even in the basal cephalochordate amphioxus that lacks major LPM-derived organ systems (Onimaru et al., 2011). These observations raise the possibility of the existence of an ancient upstream program that delineates the prospective LPM domain.In zebrafish, the LPM emerges from the ventral half of the embryo and becomes readily detectable as a patchwork of bilateral gene expression domains at the end of gastrulation (Davidson and Zon, 2004). hand2 expression marks in the anterior LPM (ALPM) the heart field and pectoral fin precursors, and a lateral-most domain within the posterior LPM (PLPM) (Perens et al., 2016; Yelon et al., 2000), wh...

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Hand2 Inhibits Kidney Specification While Promoting Vein Formation Within the Posterior Mesoderm

Cited by 7 publications

References 61 publications

Hand2 delineates mesothelium progenitors and is reactivated in mesothelioma

Hand2 delineates mesothelium progenitors and is reactivated in mesothelioma

osr1couples intermediate mesoderm cell fate with temporal dynamics of vessel progenitor cell differentiation

A conserved regulatory program drives emergence of the lateral plate mesoderm

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