BMP signaling patterns the dorsal and intermediate neural tube via regulation of homeobox and helix-loop-helix transcription factors

Development ◽  
2002 ◽  
Vol 129 (10) ◽  
pp. 2459-2472 ◽  
Author(s):  
John R. Timmer ◽  
Charlotte Wang ◽  
Lee Niswander
Keyword(s):  
Transcription Factors ◽  
Neural Tube ◽  
Transforming Growth Factor ◽  
Cell Types ◽  
Neural Cell ◽  
Bmp Signaling ◽  
Expression Domain ◽  
Cell Identity ◽  
Dorsoventral Axis ◽  
Helix Loop Helix

In the spinal neural tube, populations of neuronal precursors that express a unique combination of transcription factors give rise to specific classes of neurons at precise locations along the dorsoventral axis. Understanding the patterning mechanisms that generate restricted gene expression along the dorsoventral axis is therefore crucial to understanding the creation of diverse neural cell types. Bone morphogenetic proteins (BMPs) and other transforming growth factor β (TGFβ) proteins are expressed by the dorsal-most cells of the neural tube (the roofplate) and surrounding tissues, and evidence indicates that they play a role in assigning cell identity. We have manipulated the level of BMP signaling in the chicken neural tube to show that BMPs provide patterning information to both dorsal and intermediate cells. BMP regulation of the expression boundaries of the homeobox proteins Pax6, Dbx2 and Msx1 generates precursor populations with distinct developmental potentials. Within the resulting populations, thresholds of BMP act to set expression domain boundaries of developmental regulators of the homeobox and basic helix-loop-helix (bHLH) families, ultimately leading to the generation of a diversity of differentiated neural cell types. This evidence strongly suggests that BMPs are the key regulators of dorsal cell identity in the spinal neural tube.

Regulation of the neural patterning activity of sonic hedgehog by secreted BMP inhibitors expressed by notochord and somites

Development ◽  
2000 ◽  
Vol 127 (22) ◽  
pp. 4855-4866 ◽  
Author(s):  
K.F. Liem ◽  
T.M. Jessell ◽  
J. Briscoe
Keyword(s):  
Neural Tube ◽  
Progenitor Cell ◽  
Cell Types ◽  
Neural Cell ◽  
Bmp Signaling ◽  
Neural Cells ◽  
Cell Identity ◽  
Neuronal Fate ◽  
Ventral Neural Tube

The secretion of Sonic hedgehog (Shh) from the notochord and floor plate appears to generate a ventral-to-dorsal gradient of Shh activity that directs progenitor cell identity and neuronal fate in the ventral neural tube. In principle, the establishment of this Shh activity gradient could be achieved through the graded distribution of the Shh protein itself, or could depend on additional cell surface or secreted proteins that modify the response of neural cells to Shh. Cells of the neural plate differentiate from a region of the ectoderm that has recently expressed high levels of BMPs, raising the possibility that prospective ventral neural cells are exposed to residual levels of BMP activity. We have examined whether modulation of the level of BMP signaling regulates neural cell responses to Shh, and thus might contribute to the patterning of cell types in the ventral neural tube. Using an in vitro assay of neural cell differentiation we show that BMP signaling markedly alters neural cell responses to Shh signals, eliciting a ventral-to-dorsal switch in progenitor cell identity and neuronal fate. BMP signaling is regulated by secreted inhibitory factors, including noggin and follistatin, both of which are expressed in or adjacent to the neural plate. Conversely, follistatin but not noggin produces a dorsal-to-ventral switch in progenitor cell identity and neuronal fate in response to Shh both in vitro and in vivo. These results suggest that the specification of ventral neural cell types depends on the integration of Shh and BMP signaling activities. The net level of BMP signaling within neural tissue may be regulated by follistatin and perhaps other BMP inhibitors secreted by mesodermal cell types that flank the ventral neural tube.

PAX2 is expressed in multiple spinal cord interneurons, including a population of EN1+ interneurons that require PAX6 for their development

Development ◽  
1997 ◽  
Vol 124 (22) ◽  
pp. 4493-4503 ◽  
Author(s):  
J.D. Burrill ◽  
L. Moran ◽  
M.D. Goulding ◽  
H. Saueressig
Keyword(s):  
Spinal Cord ◽  
Transcription Factors ◽  
Ventricular Zone ◽  
Cell Types ◽  
Cell Identity ◽  
Patterning Genes ◽  
Postmitotic Neurons ◽  
Pax Family ◽  
Early Activity

Members of the PAX family of transcription factors are candidates for controlling cell identity in the spinal cord. We have morphologically analyzed cells that express one of these transcription factors, PAX2, demonstrating multiple interneuron cell types express PAX2. Two ventral populations of PAX2-expressing interneurons in the spinal cord are marked by coexpression of the transcription factors, EN1 and EVX1. Interestingly, the expression domains of PAX2, EN1 and EVX1 in postmitotic neurons correlate closely with those of Pax6 and Pax7 in the ventricular zone, implicating these patterning genes in the regulation of PAX2, EN1 and EVX1. We show that one of these patterning genes, Pax6, is required for the correct specification of ventral PAX2+ interneurons that coexpress EN1. These results demonstrate that the early activity of patterning genes in the ventricular zone determines interneuron identity in the spinal cord.

scholarly journals PLETHORA and WOX5 interaction and subnuclear localisation regulates Arabidopsis root stem cell maintenance

2019 ◽  
Author(s):  
Rebecca C. Burkart ◽  
Vivien I. Strotmann ◽  
Gwendolyn K. Kirschner ◽  
Abdullah Akinci ◽  
Laura Czempik ◽  
...  
Keyword(s):  
Stem Cell ◽  
Transcription Factors ◽  
Feedback Regulation ◽  
Cell Types ◽  
Nuclear Bodies ◽  
Quiescent Center ◽  
Expression Domain ◽  
Negative Feedback Regulation ◽  
Arabidopsis Root ◽  
Intrinsically Disordered

Maintenance and homeostasis of the stem cell niche (SCN) in the Arabidopsis root is essential for growth and development of all root cell types. The SCN is organized around a quiescent center (QC) that maintains the stemness of the cells in direct contact. The transcription factors WUSCHEL-RELATED HOMEOBOX 5 (WOX5) and the PLETHORAs (PLTs) are both expressed in the SCN where they maintain the QC and regulate the fate of the distal columella stem cells (CSCs). Although WOX5 and PLTs are known as important players in SCN maintenance, much of the necessary regulation of quiescence and division in the Arabidopsis root is not understood on a molecular level. Here, we describe the concerted mutual regulation of the key transcription factors WOX5 and PLTs on a transcriptional and protein interaction level, leading to a confinement of the WOX5 expression domain to the QC cells by negative feedback regulation. Additionally, by applying a novel SCN staining method, we demonstrate that both WOX5 and PLTs are necessary for root meristem maintenance as they regulate QC quiescence and CSC fate and show that QC divisions and CSC differentiation correlate. Moreover, we uncover that PLTs, especially PLT3, contains intrinsically disordered prion-like domains (PrDs) that are necessary for complex formation with WOX5 and its recruitment to subnuclear microdomains/nuclear bodies (NBs) in the CSCs. We propose that the partitioning of the PLT-WOX5 complexes to NBs, possibly by liquid-liquid phase separation, plays an important role during determination of CSC fate.

scholarly journals Revealing the Key Regulators of Cell Identity in the Human Adult Pancreas

2020 ◽  
Author(s):  
Lotte Vanheer ◽  
Andrea Alex Schiavo ◽  
Matthias Van Haele ◽  
Tine Haesen ◽  
Adrian Janiszewski ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Gene Regulatory Networks ◽  
Regulatory Networks ◽  
Cell Types ◽  
List Type ◽  
Cell Identity ◽  
Pancreatic Cell ◽  
Human Adult ◽  
Gene Regulatory ◽  
Cellular Identity

SUMMARYCellular identity during development is under the control of transcription factors that form gene regulatory networks. However, the transcription factors and gene regulatory networks underlying cellular identity in the human adult pancreas remain largely unexplored. Here, we integrate multiple single-cell RNA sequencing datasets of the human adult pancreas, totaling 7393 cells, and comprehensively reconstruct gene regulatory networks. We show that a network of 142 transcription factors forms distinct regulatory modules that characterize pancreatic cell types. We present evidence that our approach identifies key regulators of cell identity in the human adult pancreas. We predict that HEYL and JUND are active in acinar and alpha cells, respectively, and show that these proteins are present in the human adult pancreas as well as in human induced pluripotent stem cell-derived pancreatic cells. The comprehensive gene regulatory network atlas can be explored interactively online. We anticipate our analysis to be the starting point for a more sophisticated dissection of how transcription factors regulate cell identity in the human adult pancreas. Furthermore, given that transcription factors are major regulators of embryo development and are often perturbed in diseases, a comprehensive understanding of how transcription factors work will be relevant in development and disease biology.HIGHLIGHTS-Reconstruction of gene regulatory networks for human adult pancreatic cell types-An interactive resource to explore and visualize gene expression and regulatory states-Predicting putative transcription factors driving pancreatic cell identity-HEYL and JUND as candidate regulators of acinar and alpha cell identity, respectively

scholarly journals Single-nuclei chromatin profiling of ventral midbrain reveals cell identity transcription factors and cell-type-specific gene regulatory variation

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Yujuan Gui ◽  
Kamil Grzyb ◽  
Mélanie H. Thomas ◽  
Jochen Ohnmacht ◽  
Pierre Garcia ◽  
...  
Keyword(s):  
Gene Expression ◽  
Transcription Factors ◽  
Cell Types ◽  
Mouse Strains ◽  
Cell Type ◽  
Data Set ◽  
Cell Identity ◽  
Regulatory Variation ◽  
Ventral Midbrain ◽  
Cell Type Specific

Abstract Background Cell types in ventral midbrain are involved in diseases with variable genetic susceptibility, such as Parkinson’s disease and schizophrenia. Many genetic variants affect regulatory regions and alter gene expression in a cell-type-specific manner depending on the chromatin structure and accessibility. Results We report 20,658 single-nuclei chromatin accessibility profiles of ventral midbrain from two genetically and phenotypically distinct mouse strains. We distinguish ten cell types based on chromatin profiles and analysis of accessible regions controlling cell identity genes highlights cell-type-specific key transcription factors. Regulatory variation segregating the mouse strains manifests more on transcriptome than chromatin level. However, cell-type-level data reveals changes not captured at tissue level. To discover the scope and cell-type specificity of cis-acting variation in midbrain gene expression, we identify putative regulatory variants and show them to be enriched at differentially expressed loci. Finally, we find TCF7L2 to mediate trans-acting variation selectively in midbrain neurons. Conclusions Our data set provides an extensive resource to study gene regulation in mesencephalon and provides insights into control of cell identity in the midbrain and identifies cell-type-specific regulatory variation possibly underlying phenotypic and behavioural differences between mouse strains.

Positive and negative regulation of TGF-beta signaling

2000 ◽  
Vol 113 (7) ◽  
pp. 1101-1109 ◽  
Author(s):  
K. Miyazono
Keyword(s):  
Bone Morphogenetic Proteins ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Growth Inhibitor ◽  
Cell Types ◽  
Negative Regulation ◽  
Bmp Signaling ◽  
Tgf Beta ◽  
Transcription Complexes ◽  
Nuclear Levels

Cytokines of the transforming growth factor beta (TGF-beta) superfamily, including TGF-betas, activins and bone morphogenetic proteins (BMPs), bind to specific serine/threonine kinase receptors and transmit intracellular signals through Smad proteins. Upon ligand stimulation, Smads move into the nucleus and function as components of transcription complexes. TGF-beta and BMP signaling is regulated positively and negatively through various mechanisms. Positive regulation amplifies signals to a level sufficient for biological activity. Negative regulation occurs at the extracellular, membrane, cytoplasmic and nuclear levels. TGF-beta and BMP signaling is often regulated through negative feedback mechanisms, which limit the magnitude of signals and terminate signaling. Negative regulation is also important for formation of gradients of morphogens, which is crucial in developmental processes. In addition, other signaling pathways regulate TGF-beta and BMP signaling through cross-talk. Nearly 20 BMP isoforms have been identified, and their activities are regulated by various extracellular antagonists. Regulation of TGF-beta signaling might be tightly linked to tumor progression, since TGF-beta is a potent growth inhibitor in most cell types.

scholarly journals Homo- and heterodimerization of bHLH transcription factors balance stemness and bipotential differentiation

2019 ◽  
Author(s):  
Aleix Puig-Barbé ◽  
Joaquín de Navascués
Keyword(s):  
Stem Cells ◽  
Transcription Factors ◽  
Adult Stem Cells ◽  
Cell Types ◽  
E Proteins ◽  
Self Renewal ◽  
Helix Loop Helix ◽  
Mechanism Of Interaction ◽  
Bhlh Transcription Factors

ABSTRACTMultipotent adult stem cells must balance self-renewal with differentiation into various mature cell types. How this activity is molecularly regulated is poorly understood. By using genetic and molecular analyses in vivo, we show that a small network of basic Helix-Loop-Helix (bHLH) transcription factors controls both stemness and bi-potential differentiation in the Drosophila adult intestine. We find that homodimers of Daughterless (Da, homolog to mammalian E proteins) maintain the self-renewal of intestinal stem cells and antagonise the activity of heterodimers of Da and Scute (Sc, homolog to ASCL and known to promote intestinal secretory differentiation). We find a novel role for the HLH factor Extramacrochaetae (Emc, homolog to Id proteins), titrating Da and Sc to promote absorptive differentiation. We further show that Emc prevents committed absorptive progenitors from de-differentiating, revealing the plasticity of these cells. This mechanism of interaction partner-switching enables the active maintenance of stemness, but primes stem cells for differentiation along two alternative fates. Such regulatory logic could be recapitulated in other bipotent stem cell systems.

scholarly journals Review of Signaling Pathways Governing MSC Osteogenic and Adipogenic Differentiation

Scientifica ◽  
2013 ◽  
Vol 2013 ◽  
pp. 1-17 ◽  
Author(s):  
Aaron W. James
Keyword(s):  
Transcription Factors ◽  
Signaling Pathways ◽  
Hedgehog Signaling ◽  
Adipogenic Differentiation ◽  
Cell Types ◽  
Bmp Signaling ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Insulin Growth Factor ◽  
Related Transcription Factor

Mesenchymal stem cells (MSC) are multipotent cells, functioning as precursors to a variety of cell types including adipocytes, osteoblasts, and chondrocytes. Between osteogenic and adipogenic lineage commitment and differentiation, a theoretical inverse relationship exists, such that differentiation towards an osteoblast phenotype occurs at the expense of an adipocytic phenotype. This balance is regulated by numerous, intersecting signaling pathways that converge on the regulation of two main transcription factors: peroxisome proliferator-activated receptor-γ(PPARγ) and Runt-related transcription factor 2 (Runx2). These two transcription factors, PPARγand Runx2, are generally regarded as the master regulators of adipogenesis and osteogenesis. This review will summarize signaling pathways that govern MSC fate towards osteogenic or adipocytic differentiation. A number of signaling pathways follow the inverse balance between osteogenic and adipogenic differentiation and are generally proosteogenic/antiadipogenic stimuli. These includeβ-catenin dependent Wnt signaling, Hedgehog signaling, and NELL-1 signaling. However, other signaling pathways exhibit more context-dependent effects on adipogenic and osteogenic differentiation. These include bone morphogenic protein (BMP) signaling and insulin growth factor (IGF) signaling, which display both proosteogenic and proadipogenic effects. In summary, understanding those factors that govern osteogenic versus adipogenic MSC differentiation has significant implications in diverse areas of human health, from obesity to osteoporosis to regenerative medicine.

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