Faculty Opinions recommendation of Notch signaling regulates neural precursor allocation and binary neuronal fate decisions in zebrafish.

The Retinoblastoma protein p107 regulates the neural precursor pool in both the developing and adult brain. As p107-deficient mice exhibit enhanced levels of Hes1, we questioned whether p107 regulates neural precursor self-renewal through the repression of Hes1. p107 represses transcription at the Hes1 promoter. Despite an expanded neural precursor population, p107-null mice exhibit a striking reduction in the number of cortical neurons. Hes1 deficiency rescues neurosphere numbers in p107-null embryos. We find that the loss of a single Hes1 allele in vivo restores the number of neural precursor cells at the ventricular zone. Neuronal birthdating analysis reveals a dramatic reduction in the rate of neurogenesis, demonstrating impairment in p107−/− progenitors to commit to a neuronal fate. The loss of a single Hes1 allele restores the number of newly generated neurons in p107-deficient brains. Together, we identify a novel function for p107 in promoting neural progenitor commitment to a neuronal fate.

Download Full-text

Interleukin-1β Disturbs the Proliferation and Differentiation of Neural Precursor Cells in the Hippocampus via Activation of Notch Signaling in Postnatal Rats Exposed to Lipopolysaccharide

ACS Chemical Neuroscience ◽

10.1021/acschemneuro.9b00051 ◽

2019 ◽

Vol 10 (5) ◽

pp. 2560-2575 ◽

Cited By ~ 4

Author(s):

Qiongyu Lin ◽

Fengcai Shen ◽

Qiuping Zhou ◽

Peixian Huang ◽

Lanfen Lin ◽

...

Keyword(s):

Notch Signaling ◽

Precursor Cells ◽

Neural Precursor Cells ◽

Interleukin 1Β ◽

Neural Precursor ◽

Proliferation And Differentiation ◽

Postnatal Rats

Download Full-text

EphB2 induces proliferation and promotes a neuronal fate in adult subventricular neural precursor cells

Neuroscience Letters ◽

10.1016/j.neulet.2005.05.060 ◽

2005 ◽

Vol 385 (3) ◽

pp. 204-209 ◽

Cited By ~ 35

Author(s):

Mark Katakowski ◽

Zhenggang Zhang ◽

Ana C. deCarvalho ◽

Michael Chopp

Keyword(s):

Precursor Cells ◽

Neural Precursor Cells ◽

Neural Precursor ◽

Neuronal Fate

Download Full-text

Notch signaling acts before cell division to promote asymmetric cleavage and cell fate of neural precursor cells

Science Signaling ◽

10.1126/scisignal.2005317 ◽

2014 ◽

Vol 7 (348) ◽

pp. ra101-ra101 ◽

Cited By ~ 13

Author(s):

K. M. Bhat

Keyword(s):

Cell Division ◽

Notch Signaling ◽

Cell Fate ◽

Precursor Cells ◽

Neural Precursor Cells ◽

Neural Precursor

Download Full-text

GDNF rescues the fate of neural progenitor grafts by attenuating Notch signals in the injured spinal cord in rodents

Science Translational Medicine ◽

10.1126/scitranslmed.aau3538 ◽

2020 ◽

Vol 12 (525) ◽

pp. eaau3538 ◽

Cited By ~ 8

Author(s):

Mohamad Khazaei ◽

Christopher S. Ahuja ◽

Hiroaki Nakashima ◽

Narihito Nagoshi ◽

Lijun Li ◽

...

Keyword(s):

Spinal Cord ◽

Notch Signaling ◽

Induced Pluripotent Stem Cell ◽

Neural Progenitor Cell ◽

Neural Progenitor ◽

Neuronal Fate ◽

Cord Injury ◽

Induced Pluripotent ◽

Tissue Sparing ◽

Relevant Factors

Neural progenitor cell (NPC) transplantation is a promising strategy for the treatment of spinal cord injury (SCI). In this study, we show that injury-induced Notch activation in the spinal cord microenvironment biases the fate of transplanted NPCs toward astrocytes in rodents. In a screen for potential clinically relevant factors to modulate Notch signaling, we identified glial cell–derived neurotrophic factor (GDNF). GDNF attenuates Notch signaling by mediating delta-like 1 homolog (DLK1) expression, which is independent of GDNF’s effect on cell survival. When transplanted into a rodent model of cervical SCI, GDNF-expressing human-induced pluripotent stem cell–derived NPCs (hiPSC-NPCs) demonstrated higher differentiation toward a neuronal fate compared to control cells. In addition, expression of GDNF promoted endogenous tissue sparing and enhanced electrical integration of transplanted cells, which collectively resulted in improved neurobehavioral recovery. CRISPR-induced knockouts of the DLK1 gene in GDNF-expressing hiPSC-NPCs attenuated the effect on functional recovery, demonstrating that this effect is partially mediated through DLK1 expression. These results represent a mechanistically driven optimization of hiPSC-NPC therapy to redirect transplanted cells toward a neuronal fate and enhance their integration.

Download Full-text

miRNA suppression of a Notch repressor directs non-neuronal fate in Drosophila mechanosensory organs

The Journal of Cell Biology ◽

10.1083/jcb.201706101 ◽

2017 ◽

Vol 217 (2) ◽

pp. 571-583 ◽

Cited By ~ 1

Author(s):

Joshua Kavaler ◽

Hong Duan ◽

Rajaguru Aradhya ◽

Luis F. de Navas ◽

Brian Joseph ◽

...

Keyword(s):

Notch Signaling ◽

Cell Fate ◽

Large Scale ◽

Notch Pathway ◽

Neuronal Cell ◽

Loss Of Function ◽

Cell Specification ◽

Neuronal Fate ◽

Fate Decision ◽

Peripheral Sensory

Although there is abundant evidence that individual microRNA (miRNA) loci repress large cohorts of targets, large-scale knockout studies suggest that most miRNAs are phenotypically dispensable. Here, we identify a rare case of developmental cell specification that is highly dependent on miRNA control of an individual target. We observe that binary cell fate choice in the Drosophila melanogaster peripheral sensory organ lineage is controlled by the non-neuronally expressed mir-279/996 cluster, with a majority of notum sensory organs exhibiting transformation of sheath cells into ectopic neurons. The mir-279/996 defect phenocopies Notch loss of function during the sheath–neuron cell fate decision, suggesting the miRNAs facilitate Notch signaling. Consistent with this, mir-279/996 knockouts are strongly enhanced by Notch heterozygosity, and activated nuclear Notch is impaired in the miRNA mutant. Although Hairless (H) is the canonical nuclear Notch pathway inhibitor, and H heterozygotes exhibit bristle cell fate phenotypes reflecting gain-of-Notch signaling, H/+ does not rescue mir-279/996 mutants. Instead, we identify Insensible (Insb), another neural nuclear Notch pathway inhibitor, as a critical direct miR-279/996 target. Insb is posttranscriptionally restricted to neurons by these miRNAs, and its heterozygosity strongly suppresses ectopic peripheral nervous system neurons in mir-279/996 mutants. Thus, proper assembly of multicellular mechanosensory organs requires a double-negative circuit involving miRNA-mediated suppression of a Notch repressor to assign non-neuronal cell fate.

Download Full-text