scholarly journals Rnf149-related is an FGF/MAPK-independent regulator of pharyngeal muscle fate specification

2022 ◽  
Author(s):  
Burcu Vitrinel ◽  
Christine Vogel ◽  
Lionel Christiaen
Keyword(s):  
Cell Fate ◽  
Mapk Signaling ◽  
Integrated Analysis ◽  
Specific Gene ◽  
Loss Of Function ◽  
Pharyngeal Muscle ◽  
Knock Out ◽  
Fate Specification ◽  
Multipotent Progenitors ◽  
Pharyngeal Muscles

During embryonic development, cell fate specification gives rise to dedicated lineages that underlie tissue formation. In olfactores, which comprise tunicates and vertebrates, the cardiopharyngeal field is formed by multipotent progenitors to both cardiac and branchiomeric muscles. The ascidian Ciona is a powerful model to study the cardiopharyngeal fate specification with cellular resolution, as only 2 pairs of cardiopharyngeal multipotent progenitors give rise to the heart and to pharyngeal muscles (aka atrial siphon muscles, ASM). These progenitors are multilineage primed, in as much as they express a combination of early ASM- and heart-specific transcripts that become restricted to their corresponding precursors, following oriented asymmetric divisions. Here, we identify the primed gene Rnf149-related (Rnf149-r), which becomes restricted to the heart progenitors, but appears to regulate pharyngeal muscle fate specification in the cardiopharyngeal lineage. CRISPR/Cas9-mediated loss knock-out of Rnf149-r function impairs atrial siphon muscle morphogenesis, and down-regulates Tbx1/10 and Ebf, two key determinants of the pharyngeal muscle fate, while upregulating heart-specific gene expression. These phenotypes are reminiscent of loss of FGF-MAPK signaling in the cardiopharyngeal lineage, and integrated analysis of lineage-specific bulk RNA-seq profiling of loss-of-function perturbations identified a significant overlap between FGF-MAPK and Rnf149-r targets. However, functional interaction assays suggested the Rnf149-r does not directly modulate the activity of the FGF-MAPK-Ets1/2 pathway. Instead, we propose that Rnf149-r acts both in parallel to the FGF-MAPK signaling on shared targets, as well as on FGF-MAPK-independent targets through (a) separate pathway(s).

scholarly journals Balance between Id and E proteins regulates myeloid-versus-lymphoid lineage decisions

Blood ◽  
2009 ◽  
Vol 113 (5) ◽  
pp. 1016-1026 ◽  
Author(s):  
Shawn W. Cochrane ◽  
Ying Zhao ◽  
Robert S. Welner ◽  
Xiao-Hong Sun
Keyword(s):  
Transcription Factors ◽  
B Cell ◽  
Cell Fate ◽  
Intracellular Signaling ◽  
Specific Gene ◽  
B Cell Differentiation ◽  
E Proteins ◽  
Lymphoid Lineage ◽  
E Protein ◽  
Multipotent Progenitors

Abstract Hematopoiesis consists of a series of lineage decisions controlled by specific gene expression that is regulated by transcription factors and intracellular signaling events in response to environmental cues. Here, we demonstrate that the balance between E-protein transcription factors and their inhibitors, Id proteins, is important for the myeloid-versus-lymphoid fate choice. Using Id1-GFP knockin mice, we show that transcription of the Id1 gene begins to be up-regulated at the granulocyte-macrophage progenitor stage and continues throughout myelopoiesis. Id1 expression is also stimulated by cytokines favoring myeloid differentiation. Forced expression of Id1 in multipotent progenitors promotes myeloid development and suppresses B-cell formation. Conversely, enhancing E-protein activity by expressing a variant of E47 resistant to Id-mediated inhibition prevents the myeloid cell fate while driving B-cell differentiation from lymphoid-primed multipotent progenitors. Together, these results suggest a crucial function for E proteins in the myeloid-versus-lymphoid lineage decision.

scholarly journals MKP-3 Has Essential Roles as a Negative Regulator of the Ras/Mitogen-Activated Protein Kinase Pathway during Drosophila Development

2004 ◽  
Vol 24 (2) ◽  
pp. 573-583 ◽  
Author(s):  
Myungjin Kim ◽  
Guang-Ho Cha ◽  
Sunhong Kim ◽  
Jun Hee Lee ◽  
Jeehye Park ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Cell Fate ◽  
Photoreceptor Cells ◽  
Mapk Signaling ◽  
Negative Regulator ◽  
Mitogen Activated Protein Kinase ◽  
Loss Of Function ◽  
Wing Vein ◽  
Mitogen Activated Protein

ABSTRACT Mitogen-activated protein kinase (MAPK) phosphatase 3 (MKP-3) is a well-known negative regulator in the Ras/extracellular signal-regulated kinase (ERK)-MAPK signaling pathway responsible for cell fate determination and proliferation during development. However, the physiological roles of MKP-3 and the mechanism by which MKP-3 regulates Ras/Drosophila ERK (DERK) signaling in vivo have not been determined. Here, we demonstrated that Drosophila MKP-3 (DMKP-3) is critically involved in cell differentiation, proliferation, and gene expression by suppressing the Ras/DERK pathway, specifically binding to DERK via the N-terminal ERK-binding domain of DMKP-3. Overexpression of DMKP-3 reduced the number of photoreceptor cells and inhibited wing vein differentiation. Conversely, DMKP-3 hypomorphic mutants exhibited extra photoreceptor cells and wing veins, and its null mutants showed striking phenotypes, such as embryonic lethality and severe defects in oogenesis. All of these phenotypes were highly similar to those of the gain-of-function mutants of DERK/rl. The functional interaction between DMKP-3 and the Ras/DERK pathway was further confirmed by genetic interactions between DMKP-3 loss-of-function mutants or overexpressing transgenic flies and various mutants of the Ras/DERK pathway. Collectively, these data provide the direct evidences that DMKP-3 is indispensable to the regulation of DERK signaling activity during Drosophila development.

scholarly journals A single cell transcriptional roadmap for cardiopharyngeal fate diversification

2017 ◽  
Author(s):  
Wei Wang ◽  
Xiang Niu ◽  
Tim Stuart ◽  
Estelle Jullian ◽  
William Mauck ◽  
...  
Keyword(s):  
Single Cell ◽  
Developmental Trajectories ◽  
Mapk Signaling ◽  
Beating Heart ◽  
Pharyngeal Muscle ◽  
Evolutionary Origins ◽  
Multipotent Progenitors ◽  
Cell Diversity ◽  
Species Comparisons ◽  
Head Muscles

AbstractIn vertebrates, multipotent progenitors located in the pharyngeal mesoderm form cardiomyocytes and branchiomeric head muscles, but the dynamic gene expression programs and mechanisms underlying cardiopharyngeal multipotency and heart vs. head muscle fate choices remain elusive. Here, we used single cell genomics in the simple chordate model Ciona, to reconstruct developmental trajectories forming first and second heart lineages, and pharyngeal muscle precursors, and characterize the molecular underpinnings of cardiopharyngeal fate choices. We show that FGF-MAPK signaling maintains multipotency and promotes the pharyngeal muscle fate, whereas signal termination permits the deployment of a pan-cardiac program, shared by the first and second lineages, to define heart identity. In the second heart lineage, a Tbx1/10-Dach pathway actively suppresses the first heart lineage program, conditioning later cell diversity in the beating heart. Finally, cross-species comparisons between Ciona and the mouse evoke the deep evolutionary origins of cardiopharyngeal networks in chordates.

scholarly journals MON-719 The Cellular and Molecular Landscape of Hypothalamic Patterning and Differentiation

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Thomas Kim
Keyword(s):  
Cell Fate ◽  
Regulatory Networks ◽  
Large Scale ◽  
Molecular Mechanisms ◽  
Brain Atlas ◽  
Specific Gene ◽  
Cell Fate Specification ◽  
Human Hypothalamus ◽  
Fate Specification ◽  
Time Points

Abstract The hypothalamus is a central regulator of physiological homeostasis. During development, multiple transcription factors coordinate the patterning and specification of hypothalamic nuclei. However, the molecular mechanisms controlling hypothalamic patterning and cell fate specification are poorly understood. To identify genes that control these processes, we have used single-cell RNA sequencing (scRNA-Seq) to profile mouse hypothalamic gene expression across multiple developmental time points. We have further utilised scRNA-Seq to phenotype mutations in genes that play major roles in early hypothalamic patterning. To first understand hypothalamic development, hypothalami were collected at both embryonic (E10-E16, E18) and postnatal (PN4, PN8, PN14, PN45) time points. At early stages, when the bulk of hypothalamic patterning occurs (E11-E13), we observe a clear separation between mitotic progenitors and postmitotic neural precursor cells. We likewise observed clean segregation among cells expressing regional hypothalamic markers identified in previous large-scale analysis of hypothalamic development. This analysis reveals new region-specific markers and identifies candidate genes for selectively regulating patterning and cell fate specification in individual hypothalamic regions. With our rich dataset of developing mouse hypothalamus, we integrated our dataset with the Allen Brain Atlas in situ data, publicly available adult hypothalamic scRNA-Seq dataset to understand hierarchy of hypothalamic cell differentiation, as well as re-defining cell types of the hypothalamus. We next used scRNA-Seq to phenotype multiple mutant lines, including a line that has been extensively characterised as a proof of concept (Ctnnb1 overexpression), and lines that have not been characterised (Nkx2.1, Nkx2.2, Dlx1/2 deletion). We show that this approach can rapidly and comprehensively characterize mutants that have altered hypothalamic patterning, and in doing so, have identified multiple genes that simultaneously repress posterior hypothalamic identity while promoting prethalamic identity. This result supports a modified columnar model of organization for the diencephalon, where prethalamus and hypothalamus are situated in adjacent dorsal and ventral domains of the anterior diencephalon. These data serve as a resource for further studies of hypothalamic development and dysfunction, and able to delineate transcriptional regulatory networks of hypothalamic formation. Lastly, using our mouse hypothalamus as a guideline, we are comparing dataset of developing chicken, zebrafish and human hypothalamus, to identify evolutionarily conserved and divergent region-specific gene regulatory networks. We aim to use this knowledge and information of key molecular pathways of human hypothalamic development and produce human hypothalamus organoids.

scholarly journals TET-Mediated Epigenetic Regulation in Immune Cell Development and Disease

2021 ◽  
Vol 8 ◽  
Author(s):  
Nikolas James Tsiouplis ◽  
David Wesley Bailey ◽  
Lilly Felicia Chiou ◽  
Fiona Jane Wissink ◽  
Ageliki Tsagaratou
Keyword(s):  
Gene Expression ◽  
Cell Fate ◽  
Immune Cell ◽  
Cell Development ◽  
Dna Demethylation ◽  
Oxidation Products ◽  
Specific Gene ◽  
Loss Of Function ◽  
Cell Fate Decisions ◽  
Tet Proteins

TET proteins oxidize 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC) and further oxidation products in DNA. The oxidized methylcytosines (oxi-mCs) facilitate DNA demethylation and are also novel epigenetic marks. TET loss-of-function is strongly associated with cancer; TET2 loss-of-function mutations are frequently observed in hematological malignancies that are resistant to conventional therapies. Importantly, TET proteins govern cell fate decisions during development of various cell types by activating a cell-specific gene expression program. In this review, we seek to provide a conceptual framework of the mechanisms that fine tune TET activity. Then, we specifically focus on the multifaceted roles of TET proteins in regulating gene expression in immune cell development, function, and disease.

scholarly journals An FGF-driven feed-forward circuit patterns the cardiopharyngeal mesoderm in space and time

2017 ◽  
Author(s):  
Florian Razy-Krajka ◽  
Basile Gravez ◽  
Nicole Kaplan ◽  
Claudia Racioppi ◽  
Wei Wang ◽  
...  
Keyword(s):  
Cell Types ◽  
Mapk Signaling ◽  
Full Potential ◽  
Pharyngeal Muscle ◽  
Feed Forward ◽  
Second Heart Field ◽  
Cell Divisions ◽  
Multipotent Progenitors ◽  
Heart Field ◽  
Head Muscles

AbstractIn embryos, multipotent progenitors divide to produce distinct progeny and express their full potential. In vertebrates, multipotent cardiopharyngeal progenitors produce second-heart-field-derived cardiomyocytes, and branchiomeric skeletal head muscles. However, the mechanisms underlying these early fate choices remain largely elusive. The tunicate Ciona emerged as an attractive model to study early cardiopharyngeal development at high resolution: through two asymmetric and oriented divisions, defined cardiopharyngeal progenitors produce distinct first and second heart precursors, and pharyngeal muscle (aka atrial siphon muscle, ASM) precursors. Here, we demonstrate that differential FGF-MAPK signaling distinguishes between heart and ASM precursors. We characterize a feed-forward circuit that promotes the successive activations of essential ASM determinants, Hand-related, Tbx1/10 and Ebf. Finally, we show that coupling FGF-MAPK restriction and cardiopharyngeal network deployment with cell divisions defines the timing of gene expression and permits the emergence of diverse cell types from multipotent progenitors.

scholarly journals Primate-specific ZNF808 is essential for pancreatic development in humans

2021 ◽  
Author(s):  
Elisa De Franco ◽  
Nick DL Owens ◽  
Hossam Montaser ◽  
Matthew N Wakeling ◽  
Jonna Saarimaki-Vire ◽  
...  
Keyword(s):  
Transposable Elements ◽  
Cell Fate ◽  
Zinc Finger Protein ◽  
Critical Role ◽  
Specific Gene ◽  
Loss Of Function ◽  
Pancreatic Development ◽  
Extreme Phenotypes ◽  
Pancreatic Agenesis

Identifying genes linked to extreme phenotypes in humans has the potential to highlight new biological processes fundamental for human development. Here we report the identification of homozygous loss of function variants in the primate-specific gene ZNF808 as a cause of pancreatic agenesis. ZNF808 is a member of the KRAB zinc finger protein (KZFPs) family, a large and rapidly evolving group of epigenetic silencers that target transposable elements. Loss of ZNF808 in vitro results in aberrant activation of many transposable elements it normally represses during early pancreas development. We show that this results in inappropriate specification of cell fate with induction of genes associated with liver endoderm and a loss of pancreatic identity. This suggests that ZNF808 and its transposable element targets play a critical role in cell fate specification during human pancreatic development. This is the first report of loss of a primate-specific gene causing a congenital developmental disease and highlights the essential role of ZNF808 for pancreatic development in humans.

The Caenorhabditis elegans NK-2 homeobox gene ceh-22 activates pharyngeal muscle gene expression in combination with pha-1 and is required for normal pharyngeal development

Development ◽  
1997 ◽  
Vol 124 (20) ◽  
pp. 3965-3973 ◽  
Author(s):  
P.G. Okkema ◽  
E. Ha ◽  
C. Haun ◽  
W. Chen ◽  
A. Fire
Keyword(s):  
Gene Expression ◽  
Caenorhabditis Elegans ◽  
Muscle Development ◽  
Synergistic Effects ◽  
Chain Gene ◽  
Loss Of Function ◽  
Pharyngeal Muscle ◽  
Muscle Gene Expression ◽  
Pharyngeal Muscles ◽  
Muscle Gene

Pharyngeal muscle development in the nematode Caenorhabditis elegans appears to share similarities with cardiac muscle development in other species. We have previously described CEH-22, an NK-2 class homeodomain transcription factor similar to Drosophila tinman and vertebrate Nkx2-5, which is expressed exclusively in the pharyngeal muscles. In vitro, CEH-22 binds the enhancer from myo-2, a pharyngeal muscle-specific myosin heavy chain gene. In this paper, we examine the role CEH-22 plays in pharyngeal muscle development and gene activation by (a) ectopically expressing ceh-22 in transgenic C. elegans and (b) examining the phenotype of a ceh-22 loss-of-function mutant. These experiments indicate that CEH-22 is an activator of myo-2 expression and that it is required for normal pharyngeal muscle development. However, ceh-22 is necessary for neither formation of the pharyngeal muscles, nor for myo-2 expression. Our data suggest parallel and potentially compensating pathways contribute to pharyngeal muscle differentiation. We also examine the relationship between ceh-22 and the pharyngeal organ-specific differentiation gene pha-1. Mutations in ceh-22 and pha-1 have strongly synergistic effects on pharyngeal muscle gene expression; in addition, a pha-1 mutation enhances the lethal phenotype caused by a mutation in ceh-22. Wild-type pha-1 is not required for the onset of ceh-22 expression but it appears necessary for maintained expression of ceh-22.

scholarly journals Combinatorial chromatin dynamics foster accurate cardiopharyngeal fate choices

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
Claudia Racioppi ◽  
Keira A Wiechecki ◽  
Lionel Christiaen
Keyword(s):  
Gene Expression ◽  
Specific Activity ◽  
Expression Profiles ◽  
Regulatory Elements ◽  
Chromatin Accessibility ◽  
Specific Gene ◽  
Specific Expression ◽  
Pharyngeal Muscle ◽  
Chromatin Dynamics ◽  
Multipotent Progenitors

During embryogenesis, chromatin accessibility profiles control lineage-specific gene expression by modulating transcription, thus impacting multipotent progenitor states and subsequent fate choices. Subsets of cardiac and pharyngeal/head muscles share a common origin in the cardiopharyngeal mesoderm, but the chromatin landscapes that govern multipotent progenitors competence and early fate choices remain largely elusive. Here, we leveraged the simplicity of the chordate model Ciona to profile chromatin accessibility through stereotyped transitions from naive Mesp+ mesoderm to distinct fate-restricted heart and pharyngeal muscle precursors. An FGF-Foxf pathway acts in multipotent progenitors to establish cardiopharyngeal-specific patterns of accessibility, which govern later heart vs. pharyngeal muscle-specific expression profiles, demonstrating extensive spatiotemporal decoupling between early cardiopharyngeal enhancer accessibility and late cell-type-specific activity. We found that multiple cis-regulatory elements, with distinct chromatin accessibility profiles and motif compositions, are required to activate Ebf and Tbx1/10, two key determinants of cardiopharyngeal fate choices. We propose that these ‘combined enhancers’ foster spatially and temporally accurate fate choices, by increasing the repertoire of regulatory inputs that control gene expression, through either accessibility and/or activity.

scholarly journals A context-dependent bifurcation in the Pointed transcriptional effector network contributes specificity and robustness to retinal cell fate acquisition

PLoS Genetics ◽  
2020 ◽  
Vol 16 (11) ◽  
pp. e1009216
Author(s):  
Chudong Wu ◽  
Jean-François Boisclair Lachance ◽  
Michael Z. Ludwig ◽  
Ilaria Rebay
Keyword(s):  
Cell Fate ◽  
Expression Patterns ◽  
Transcriptional Response ◽  
Mapk Signaling ◽  
Mitogen Activated Protein Kinase ◽  
Null Alleles ◽  
Retinal Cell ◽  
Intrinsic Activity ◽  
Fate Specification ◽  
Mapk Activity

Spatiotemporally precise and robust cell fate transitions, which depend on specific signaling cues, are fundamental to the development of appropriately patterned tissues. The fidelity and precision with which photoreceptor fates are recruited in the Drosophila eye exemplifies these principles. The fly eye consists of a highly ordered array of ~750 ommatidia, each of which contains eight distinct photoreceptors, R1-R8, specified sequentially in a precise spatial pattern. Recruitment of R1-R7 fates requires reiterative receptor tyrosine kinase / mitogen activated protein kinase (MAPK) signaling mediated by the transcriptional effector Pointed (Pnt). However the overall signaling levels experienced by R2-R5 cells are distinct from those experienced by R1, R6 and R7. A relay mechanism between two Pnt isoforms initiated by MAPK activation directs the universal transcriptional response. Here we ask how the generic Pnt response is tailored to these two rounds of photoreceptor fate transitions. We find that during R2-R5 specification PntP2 is coexpressed with a closely related but previously uncharacterized isoform, PntP3. Using CRISPR/Cas9-generated isoform specific null alleles we show that under otherwise wild type conditions, R2-R5 fate specification is robust to loss of either PntP2 or PntP3, and that the two activate pntP1 redundantly; however under conditions of reduced MAPK activity, both are required. Mechanistically, our data suggest that intrinsic activity differences between PntP2 and PntP3, combined with positive and unexpected negative transcriptional auto- and cross-regulation, buffer first-round fates against conditions of compromised RTK signaling. In contrast, in a mechanism that may be adaptive to the stronger signaling environment used to specify R1, R6 and R7 fates, the Pnt network resets to a simpler topology in which PntP2 uniquely activates pntP1 and auto-activates its own transcription. We propose that differences in expression patterns, transcriptional activities and regulatory interactions between Pnt isoforms together facilitate context-appropriate cell fate specification in different signaling environments.

Sign in / Sign up

Export Citation Format

Share Document