Notch Activity Modulates the Responsiveness of Neural Progenitors to Sonic Hedgehog Signaling

Summary Throughout the developing nervous system, neural stem and progenitor cells give rise to diverse classes of neurons and glia in a spatially and temporally coordinated manner. In the ventral spinal cord, much of this diversity emerges through the morphogen actions of Sonic hedgehog (Shh). Interpretation of the Shh gradient depends on both the amount of ligand and duration of exposure, but the mechanisms permitting prolonged responses to Shh are not well understood. We demonstrate that Notch signaling plays an essential role in this process, enabling neural progenitors to attain sufficiently high levels of Shh pathway activity needed to direct the ventral-most cell fates. Notch activity regulates subcellular localization of the Shh receptor Patched1, gating the translocation of the key effector Smoothened to primary cilia and its downstream signaling activities. These data reveal an unexpected role for Notch shaping the interpretation of the Shh morphogen gradient and influencing cell fate determination.

• Publication year

  2015

• Venue

  Developmental Cell

• Publication date

  2015-05-26

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.1016/j.devcel.2015.03.005PMID 25936505PMCID 4449290
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• From classical to current: analyzing peripheral nervous system and spinal cord lineage and fate.

  2015cited by this paper
• Requirement of Smurf-mediated endocytosis of Patched1 in sonic hedgehog signal reception

  2014cited by this paper
• The mechanisms of Hedgehog signalling and its roles in development and disease

  2013cited by this paper
• The ciliary G-protein-coupled receptor Gpr161 negatively regulates the Sonic hedgehog pathway via cAMP signaling.

  2013cited by this paper
• SoxB1-driven transcriptional network underlies neural-specific interpretation of morphogen signals

  2013cited by this paper
• PLZF Regulates Fibroblast Growth Factor Responsiveness and Maintenance of Neural Progenitors

  2013cited by this paper
• Structure and function of the Smoothened extracellular domain in vertebrate Hedgehog signaling

  2013cited by this paper
• Attenuation of Notch and Hedgehog Signaling Is Required for Fate Specification in the Spinal Cord

  2012cited by this paper
• Mechanistic differences in the transcriptional interpretation of local and long-range Shh morphogen signaling.

  2012cited by this paper
• IFT25 links the signal-dependent movement of Hedgehog components to intraflagellar transport.

  2012influential reference
• Proteomic analysis of mammalian primary cilia.

  2012cited by this paper
• Neural-specific Sox2 input and differential Gli-binding affinity provide context and positional information in Shh-directed neural patterning.

  2012cited by this paper
• Foxp-mediated suppression of N-cadherin regulates neuroepithelial character and progenitor maintenance in the CNS.

  2012cited by this paper
• Sox9 and NFIA coordinate a transcriptional regulatory cascade during the initiation of gliogenesis.

  2012cited by this paper
• Gene Regulatory Logic for Reading the Sonic Hedgehog Signaling Gradient in the Vertebrate Neural Tube

  2012cited by this paper
• Modeling human disease in humans: the ciliopathies.

  2011cited by this paper
• NPHP4, a cilia-associated protein, negatively regulates the Hippo pathway

  2011cited by this paper
• Subcellular Spatial Regulation of Canonical Wnt Signaling at the Primary Cilium

  2011cited by this paper
• Notch in the vertebrate nervous system: an old dog with new tricks.

  2011influential reference
• A role for the primary cilium in Notch signaling and epidermal differentiation during skin development.

  2011cited by this paper
• Morphogen gradients: from generation to interpretation.

  2011cited by this paper
• Direct inhibition of the NOTCH transcription factor complex

  2010cited by this paper
• Primary cilia regulate mTORC1 activity and cell size through Lkb1

  2010cited by this paper
• Dynamic Assignment and Maintenance of Positional Identity in the Ventral Neural Tube by the Morphogen Sonic Hedgehog

  2010cited by this paper
• Developmental genetics of vertebrate glial–cell specification

  2010cited by this paper
• A mechanism for vertebrate Hedgehog signaling: recruitment to cilia and dissociation of SuFu–Gli protein complexes

  2010cited by this paper
• Distinct Sonic Hedgehog signaling dynamics specify floor plate and ventral neuronal progenitors in the vertebrate neural tube.

  2010cited by this paper
• Direct inhibition of the NOTCH transcription factor complex

  2009cited by this paper
• Differentiation of human oligodendrocytes from pluripotent stem cells

  2009cited by this paper
• Establishing and interpreting graded Sonic Hedgehog signaling during vertebrate neural tube patterning: the role of negative feedback.

  2009influential reference
• Temporal dynamics of patterning by morphogen gradients.

  2009cited by this paper
• Dynamic regulation of Notch signaling in neural progenitor cells.

  2009cited by this paper
• Progenitor cell proliferation in the retina is dependent on Notch-independent Sonic hedgehog/Hes1 activity

  2009cited by this paper
• Hedgehog signal transduction by Smoothened: Pharmacologic evidence for a 2-step activation process

  2009cited by this paper
• Chapter Two Intraflagellar Transport (IFT)

  2008cited by this paper
• Coordinated actions of the forkhead protein Foxp1 and Hox proteins in the columnar organization of spinal motor neurons.

  2008influential reference
• Disruption of the PACAP gene promotes medulloblastoma in ptc1 mutant mice.

  2008cited by this paper
• Pattern formation in the vertebrate neural tube: a sonic hedgehog morphogen-regulated transcriptional network

  2008influential reference
• Identification of positionally distinct astrocyte subtypes whose identities are specified by a homeodomain code.

  2008influential reference
• Sonic Hedgehog regulates Hes1 through a novel mechanism that is independent of canonical Notch pathway signalling

  2008cited by this paper
• Regulatory pathways linking progenitor patterning, cell fates and neurogenesis in the ventral neural tube

  2008influential reference
• Intraflagellar transport (IFT) role in ciliary assembly, resorption and signalling.

  2008cited by this paper
• Characterization of progenitor domains in the developing mouse thalamus

  2007cited by this paper
• Physiological Notch signaling promotes gliogenesis in the developing peripheral and central nervous systems

  2007cited by this paper
• Cilia and developmental signaling.

  2007cited by this paper
• Patched 1 Regulates Hedgehog Signaling at the Primary Cilium

  2007influential reference
• Interpretation of the sonic hedgehog morphogen gradient by a temporal adaptation mechanism

  2007influential reference
• The Hes gene family: repressors and oscillators that orchestrate embryogenesis

  2007cited by this paper
• Patched1 Regulates Hedgehog Signaling at the Primary Cilium

  2007cited by this paper
• Morphogen to mitogen: the multiple roles of hedgehog signalling in vertebrate neural development

  2006cited by this paper
• HES1 Inhibits Cycling of Hematopoietic Progenitor Cells via DNA Binding

  2006cited by this paper
• Purmorphamine activates the Hedgehog pathway by targeting Smoothened

  2006cited by this paper
• Specification of astrocytes by bHLH protein SCL in a restricted region of the neural tube

  2005cited by this paper
• Multiple origins of Cajal-Retzius cells at the borders of the developing pallium

  2005cited by this paper
• PDGFRalphaalpha signaling is regulated through the primary cilium in fibroblasts.

  2005cited by this paper
• A gradient of Gli activity mediates graded Sonic Hedgehog signaling in the neural tube.

  2005cited by this paper
• Vertebrate Smoothened functions at the primary cilium

  2005cited by this paper
• Hes genes regulate size, shape and histogenesis of the nervous system by control of the timing of neural stem cell differentiation

  2004cited by this paper
• The vertebrate primary cilium is a sensory organelle.

  2003cited by this paper
• A requirement for retinoic acid-mediated transcriptional activation in ventral neural patterning and motor neuron specification.

  2003cited by this paper
• Lentiviral vectors with two independent internal promoters transfer high-level expression of multiple transgenes to human hematopoietic stem-progenitor cells.

  2003cited by this paper
• Notch Activation Suppresses Fibroblast Growth Factor-dependent Cellular Transformation*

  2003cited by this paper
• Notch signaling controls multiple steps of pancreatic differentiation

  2003influential reference
• Cross-Repressive Interaction of the Olig2 and Nkx2.2 Transcription Factors in Developing Neural Tube Associated with Formation of a Specific Physical Complex

  2003cited by this paper
• The role of notch in promoting glial and neural stem cell fates.

  2002cited by this paper
• Notch signaling promotes astrogliogenesis via direct CSL‐mediated glial gene activation

  2002cited by this paper
• A mitogen gradient of dorsal midline Wnts organizes growth in the CNS.

  2002cited by this paper
• Small molecule modulation of Smoothened activity

  2002cited by this paper
• Human GLI2 and GLI1 are part of a positive feedback mechanism in Basal Cell Carcinoma

  2002cited by this paper
• Inducible gene knockout of transcription factor recombination signal binding protein-J reveals its essential role in T versus B lineage decision.

  2002cited by this paper
• A γ‐secretase inhibitor blocks Notch signaling in vivo and causes a severe neurogenic phenotype in zebrafish

  2002cited by this paper
• An instructive function for Notch in promoting gliogenesis in the zebrafish retina.

  2001cited by this paper
• Coordinate regulation of motor neuron subtype identity and pan-neuronal properties by the bHLH repressor Olig2.

  2001influential reference
• New protease inhibitors prevent γ-secretase-mediated production of Aβ40/42 without affecting Notch cleavage

  2001cited by this paper
• Activation of EGFP expression by Cre-mediated excision in a new ROSA26 reporter mouse strain.

  2001influential reference
• Combinatorial roles of olig2 and neurogenin2 in the coordinated induction of pan-neuronal and subtype-specific properties of motoneurons.

  2001cited by this paper
• New protease inhibitors prevent gamma-secretase-mediated production of Abeta40/42 without affecting Notch cleavage.

  2001cited by this paper
• Basic helix-loop-helix transcription factors regulate the neuroendocrine differentiation of fetal mouse pulmonary epithelium.

  2000cited by this paper
• Radial glial identity is promoted by Notch1 signaling in the murine forebrain.

  2000cited by this paper
• A homeodomain protein code specifies progenitor cell identity and neuronal fate in the ventral neural tube.

  2000cited by this paper
• Effects of oncogenic mutations in Smoothened and Patched can be reversed by cyclopamine

  2000cited by this paper
• A Homeodomain Protein Code Specifies Progenitor Cell Identity and Neuronal Fate in the Ventral Neural Tube

  2000cited by this paper
• Functional gamma‐secretase inhibitors reduce beta‐amyloid peptide levels in brain

  2000cited by this paper
• rax, Hes1, and notch1 promote the formation of Müller glia by postnatal retinal progenitor cells.

  2000cited by this paper
• Requirement for the homeobox gene Hb9 in the consolidation of motor neuron identity.

  1999cited by this paper
• Active suppression of interneuron programs within developing motor neurons revealed by analysis of homeodomain factor HB9.

  1999cited by this paper
• Homeobox gene Nkx2.2 and specification of neuronal identity by graded Sonic hedgehog signalling

  1999cited by this paper
• Acknowledgments

  1998cited by this paper
• Notch receptor activation inhibits oligodendrocyte differentiation.

  1998cited by this paper
• Pax6 controls progenitor cell identity and neuronal fate in response to graded Shh signaling.

  1997cited by this paper
• Two critical periods of Sonic Hedgehog signaling required for the specification of motor neuron identity.

  1996cited by this paper
• The winged-helix transcription factor HNF-3 beta is required for notochord development in the mouse embryo.

  1994cited by this paper
• Topographic organization of embryonic motor neurons defined by expression of LIM homeobox genes.

  1994cited by this paper
• Control of cell pattern in the neural tube: motor neuron induction by diffusible factors from notochord and floor plate.

  1993cited by this paper
• Mammalian achaete-scute homolog 1 is transiently expressed by spatially restricted subsets of early neuroepithelial and neural crest cells.

  1991cited by this paper
• Beiträge zur Kenntniss einiger Drüsen und Epithelien

  1898cited by this paper
• Cellular and Molecular Life Sciences the Multiple Activities of Bmps during Spinal Cord Development

  year unknowncited by this paper

• A transcriptomic resource for glial GABA-associated ASH neuronal aging and candidate pathways

  2026cites this paper
• Bidirectional interaction between protocadherin 8 and the transcription factor Dbx1 regulates cerebral cortex development

  2026cites this paper
• Primary cilia in neural development and disease.

  2025cites this paper
• Primary cilia and cancer: a tale of many faces

  2025cites this paper
• Chromosomal Microarray Analysis in Spina Bifida: Genetic Heterogeneity and Its Clinical Implications

  2025cites this paper
• Mechanistic logic and timing of retinal bipolar cell class and type specification

  2025cites this paper
• Remodelling of supernumerary leaflet primordia leads to bicuspid aortic valve caused by loss of primary cilia

  2025cites this paper
• Epigenetic priming of neural progenitors by Notch enhances Sonic hedgehog signaling and establishes gliogenic competence

  2025cites this paper
• Development of Oligodendroglia and Myelin.

  2025cites this paper
• Epigenetic priming of neural progenitors by Notch enhances Sonic hedgehog signaling and establishes gliogenic competence

  2025cites this paper
• Bidirectional interaction between Protocadherin 8 and transcription factor Dbx1 regulates cerebral cortex development

  2025cites this paper
• Primary cilia-associated signalling in squamous cell carcinoma of head and neck region

  2024cites this paper
• Quiescent Adult Neural Stem Cells: Developmental Origin and Regulatory Mechanisms

  2024cites this paper
• Brain organoid protocols and limitations

  2024cites this paper
• Intrinsic and extrinsic actions of human neural progenitors with SUFU inhibition promote tissue repair and functional recovery from severe spinal cord injury

  2024cites this paper
• Neuroepithelial organoid patterning is mediated by a neighborhood watch mechanism.

  2023cites this paper
• Transcriptional control of motor pool formation and motor circuit connectivity by the LIM-HD protein Isl2

  2023cites this paper
• Presenilin natural antisense transcription in the sea urchin: a general control of gene expression during development?

  2023cites this paper
• Pharmacological modulation of Sonic Hedgehog signaling pathways in Angiogenesis: A mechanistic perspective.

  2023cites this paper
• Gli2 and Gli3 Regulate Horizontal Basal Cell-Mediated Regeneration of the Olfactory Epithelium

  2023cites this paper
• Primary cilia: Structure, dynamics, and roles in cancer cells and tumor microenvironment

  2023cites this paper
• The Cross-Talks Among Bone Morphogenetic Protein (BMP) Signaling and Other Prominent Pathways Involved in Neural Differentiation

  2022cites this paper
• Transcriptional control of motor pool formation and motor circuit connectivity by the LIM-HD protein Isl2

  2022cites this paper
• The Symmetry of Neural Stem Cell and Progenitor Divisions in the Vertebrate Brain

  2022cites this paper
• Disruption of GMNC-MCIDAS multiciliogenesis program is critical in choroid plexus carcinoma development

  2022cites this paper
• Dbx1 controls the development of astrocytes of the intermediate spinal cord by modulating Notch signaling

  2022cites this paper
• A53T α-synuclein induces neurogenesis impairment and cognitive dysfunction in line M83 transgenic mice and reduces the proliferation of embryonic neural stem cells.

  2022cites this paper
• Flags, landscapes and signaling: contact-mediated inter-cellular interactions enable plasticity in fate determination driven by positional information

  2022influential citation
• Neuroepithelial organoid patterning is mediated by Wnt-driven Turing mechanism

  2021influential citation
• Dorsal commissural axon guidance in the developing spinal cord.

  2021cites this paper
• GAS1 is required for NOTCH-dependent facilitation of SHH signaling in the ventral forebrain neuroepithelium

  2021cites this paper
• Precision of morphogen-driven tissue patterning during development is enhanced through contact-mediated cellular interactions.

  2021cites this paper
• A precise regulation of presenilin expression is required for the sea urchin early development.

  2021cites this paper
• Epigenetically Mediated Ciliogenesis and Cell Cycle Regulation, and Their Translational Potential

  2021cites this paper
• Gene-teratogen interactions influence the penetrance of birth defects by altering Hedgehog signaling strength

  2021influential citation
• Resveratrol-mediated neurorestoration after cerebral ischemic injury - Sonic Hedgehog signaling pathway.

  2021cites this paper
• SORBS2 is a genetic factor contributing to cardiac malformation of 4q deletion syndrome patients

  2021cites this paper
• Temporal cell fate determination in the spinal cord is mediated by the duration of Notch signalling

  2021cites this paper
• Getting in touch with your senses: Mechanisms specifying sensory interneurons in the dorsal spinal cord

  2021cites this paper
• Sonic hedgehog expands neural stem cells in the neocortical region leading to an expanded and wrinkled neocortical surface

  2021cites this paper
• Comprehending the crosstalk between Notch, Wnt and Hedgehog signaling pathways in oral squamous cell carcinoma - clinical implications

  2021cites this paper
• Contact-mediated cellular communication supplements positional information to regulate spatial patterning during development.

  2021cites this paper
• Trp53 and Rb1 regulate autophagy and ligand-dependent Hedgehog signaling.

  2020cites this paper
• Daam2 couples translocation and clustering of Wnt receptor signalosomes through Rac1

  2020cites this paper
• Zfp36l1 and Zfp36l2 balances proliferation and differentiation in the developing retina

  2020cites this paper
• Sox17 Promotes Oligodendrocyte Regeneration by Dual Modulation of Hedgehog and Wnt Signaling

  2020cites this paper
• Complex crosstalk of Notch and Hedgehog signalling during the development of the central nervous system

  2020cites this paper
• High-throughput 3D screening for differentiation of hPSC-derived cell therapy candidates

  2020cites this paper
• The novel testicular enrichment protein Cfap58 is required for Notch-associated ciliogenesis

  2020cites this paper
• Notch pathway up-regulation via curcumin mitigates bisphenol-A (BPA) induced alterations in hippocampal oligodendrogenesis.

  2020cites this paper
• SORBS2 is a genetic factor contributing to cardiac malformation of 4q deletion syndrome

  2020influential citation
• The specification and generation of neurons in the ventral spinal cord

  2020cites this paper
• Prdm8 regulates pMN progenitor specification for motor neuron and oligodendrocyte fates by modulating the Shh signaling response

  2020cites this paper
• Beyond its antioxidant properties: Quercetin targets multiple signalling pathways in hepatocellular carcinoma in rats.

  2019cites this paper
• Sonic hedgehog signaling controls dentate gyrus patterning and adult neurogenesis in the hippocampus

  2019cites this paper
• A Notch-mediated, temporal asymmetry in BMP pathway activation promotes photoreceptor subtype diversification

  2019cites this paper
• Estrogen-mediated protection against coronary heart disease: The role of the Notch pathway.

  2019cites this paper
• New perspectives on the mechanisms establishing the dorsal-ventral axis of the spinal cord.

  2019cites this paper
• Arsenic Trioxide and (−)-Gossypol Synergistically Target Glioma Stem-Like Cells via Inhibition of Hedgehog and Notch Signaling

  2019cites this paper
• Stage‐dependent regulation of oligodendrocyte development and enhancement of myelin repair by dominant negative Master‐mind 1 protein

  2019cites this paper
• Evolution of vertebrate spinal cord patterning

  2019cites this paper
• Wnt, Notch, and TGF-β Pathways Impinge on Hedgehog Signaling Complexity: An Open Window on Cancer

  2019cites this paper
• FMRP Modulates Neural Differentiation through m6A-Dependent mRNA Nuclear Export

  2019cites this paper
• The Hedgehog receptor Patched1 regulates proliferation, neurogenesis, and axon guidance in the embryonic spinal cord.

  2019cites this paper
• Mark1 regulates distal airspace expansion through type I pneumocyte flattening in lung development

  2019cites this paper
• Hes1 regulates anagen initiation and hair follicle regeneration through modulation of hedgehog signaling

  2019cites this paper
• Etude du rôle de la voie NOTCH dans la régulation de Shh au cours du développement du cerveau antérieur chez les vertébrés

  2019influential citation
• Distinct temporal requirements for Sonic hedgehog signaling in development of the tuberal hypothalamus

  2018cites this paper
• Notch and Stem Cells.

  2018cites this paper
• Osteoarthritis-Like Changes in Bardet–Biedl Syndrome Mutant Ciliopathy Mice (Bbs1M390R/M390R): Evidence for a Role of Primary Cilia in Cartilage Homeostasis and Regulation of Inflammation

  2018cites this paper
• Neural stem cell heterogeneity in the mammalian forebrain

  2018cites this paper
• Alterations in Morphology and Adult Neurogenesis in the Dentate Gyrus of Patched1 Heterozygous Mice

  2018cites this paper
• University of Dundee Cell biological mechanisms regulating chick neurogenesis

  2018cites this paper
• Cell biological mechanisms regulating chick neurogenesis.

  2018cites this paper
• Notch signalling maintains Hedgehog responsiveness via a Gli-dependent mechanism during spinal cord patterning in zebrafish

  2018cites this paper
• Ciliary signalling in cancer

  2018cites this paper
• Targeting Smoothened as a New Frontier in the Functional Recovery of Central Nervous System Demyelinating Pathologies

  2018cites this paper
• Notch and Wnt Dysregulation and Its Relevance for Breast Cancer and Tumor Initiation

  2018cites this paper
• Oncometabolite induced primary cilia loss in pheochromocytoma

  2018cites this paper
• A Novel 2‐Phenylamino‐Quinazoline‐Based Compound Expands the Neural Stem Cell Pool and Promotes the Hippocampal Neurogenesis and the Cognitive Ability of Adult Mice

  2018cites this paper
• Sequential Specification of Oligodendrocyte Lineage Cells by Distinct Levels of Hedgehog and Notch Signaling

  2018cites this paper
• Resveratrol Activated Sonic Hedgehog Signaling to Enhance Viability of NIH3T3 Cells in Vitro via Regulation of Sirt1

  2018cites this paper
• Mathematically universal and biologically consistent astrocytoma genotype encodes for transformation and predicts survival phenotype

  2018cites this paper
• Cadherin de-adhesion: consequences and mechanisms

  2017influential citation
• The primary cilium as a signaling nexus for growth plate function and subsequent skeletal development

  2017cites this paper
• Redefining the Role of Netrin1 as an Axon Guidance Cue in the Developing Spinal Cord

  2017cites this paper
• APC sets the Wnt tone necessary for cerebral cortical progenitor development

  2017cites this paper
• Radial Extracorporeal Shock Wave Therapy Enhances the Proliferation and Differentiation of Neural Stem Cells by Notch, PI3K/AKT, and Wnt/β-catenin Signaling

  2017cites this paper
• Notch pathway signaling in the skin antagonizes Merkel cell development.

  2017cites this paper
• Primary Cilia and Coordination of Receptor Tyrosine Kinase (RTK) and Transforming Growth Factor β (TGF-β) Signaling.

  2017influential citation
• Primary Cilium-Dependent Signaling Mechanisms

  2017cites this paper
• Resveratrol Enhances Neurite Outgrowth and Synaptogenesis Via Sonic Hedgehog Signaling Following Oxygen-Glucose Deprivation/Reoxygenation Injury

  2017cites this paper
• Notch Signaling in Development, Tissue Homeostasis, and Disease.

  2017cites this paper
• Network-Based Method for Identifying Co-Regeneration Genes in Bone, Dentin, Nerve and Vessel Tissues

  2017cites this paper
• Adult hippocampal neurogenesis: Is it the alpha and omega of antidepressant action?

  2017cites this paper
• BMPs direct sensory interneuron identity in the developing spinal cord using signal-specific not morphogenic activities

  2017influential citation
• Functions of the Prion Protein.

  2017cites this paper
• Basal cell carcinoma pathogenesis and therapy involving hedgehog signaling and beyond

  2017influential citation
• Netrin1 Produced by Neural Progenitors, Not Floor Plate Cells, Is Required for Axon Guidance in the Spinal Cord.

  2017influential citation
• Crosstalk between Notch and Sonic hedgehog signaling in a mouse model of amyotrophic lateral sclerosis

  2017cites this paper