Numb and Numblike control cell number during vertebrate neurogenesis

doi:10.1016/S0166-2236(03)00166-8

Trends in Neurosciences

Volume 26, Issue 8, August 2003, Pages 395-396

https://doi.org/10.1016/S0166-2236(03)00166-8 Get rights and content

Abstract

A fundamental problem in nervous system development is how to control progenitor-cell divisions to generate the correct number of cells for the mature brain and spinal cord. A recent report by Petersen and colleagues has identified an essential role for Numb and a related protein, Numblike, in this process. This study demonstrates that Numb and Numblike function to maintain the self-renewal properties of neural progenitor cells in the vertebrate neural tube.

Section snippets

Opposing roles suggested for Numb in neural development

Cell divisions resulting in proteins being asymmetrically distributed in the daughter cells are thought to play a key role in these fate decisions. In Drosophila, multiple asymmetrically localized proteins have been identified [3]. One of these, called Numb, has been shown to be important in cell fate decisions, and in some of these choice points Numb functions through inhibition of Notch signaling 4, 5. Vertebrate Numb, and a related protein, Numblike (Nbl), have been identified 6, 7 and, like

A role for Numb and Nbl in maintaining the progenitor state

Teasing out the different functions of Numb will require additional creative approaches. To this end, a recent knockout provides convincing evidence that Numb, and the related Nbl, play a key role in maintaining neural progenitor cells [13]. This study, with its elegant use of mouse mutants, has bypassed the early lethality of the numb/nbl double mutant, allowing a detailed analysis of the consequences of loss of these two related proteins at early stages of neurogenesis. For this study, nbl

Unresolved issues

This study, while demonstrating a role for Numb and Nbl in maintaining the progenitor state, does not preclude the additional proposal that Numb biases cells to the neuronal fate at different stages in different cellular contexts. The conditional numb/nbl double knockout will be a powerful tool to address later functions of these proteins, by driving Cre at stages of neurogenesis later than that used for the recent study. Additional questions concerning the mechanism of Numb function still

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Cited by (32)

Numb deficiency impairs retinal structure and visual function in mice
2022, Experimental Eye Research
Citation Excerpt :
Numb is an adapter protein that engages in many signaling pathways and interacts with molecules including Notch, Hedgehog, and p53(Verdi, Schmandt et al., 1996; Dho, French et al., 1999; Gulino, Di Marcotullio et al., 2010). Numblike (Nbl) acts functionally redundant with its homolog Numb in mammals, and various transgene studies in mouse cerebral progenitors revealed that Numb and Nbl are essential for neurogenesis(Zhong, Jiang et al., 1997; Johnson, 2003). As knockout of Numb or Nbl alone did not affect the retinal normal architecture and function, our studies are based on Numb and Nbl both conditional double-knockout in the retina.
Numb is expressed in the progenitor and mature neurons throughout the development progress of the retina. We attempted to investigate the role of Numb in the retina and visual system, and the effects of Numb deficiency on retinal structure and visual function.
Conditional Numb/Nbl double-knockout mice were generated to observe the retinal damage in Numb deficiency mice. HE staining and immunofluorescence stain were used to observe the structural and molecular changes. The visual function was assessed by electroretinogram (ERG) and optomotor response (OMR). RNA-Seq and RT-PCR were used to detect the differential expression of genes and the related signaling pathways.
Inactivation of Numb/Nbl induces eye apoptosis and retinal neurons impairment observed by HE staining and immunofluorescence stain. The impaired retinal structure and visual function were assessed by ERG and OMR. RNA-seq analysis indicated loss of photoreceptors, synapses and phototransduction related molecules. Immunofluorescence stain of molecular markers recoverin, arrestin, rhodopsin showed disrupted structural integrity of photoreceptors. Additional bipolar cells and synapses related molecular markers indicate synaptic connections were damaged in Numb deficiency mice.
Inactivation of Numb/Nbl induces eye apoptosis and retinal neurons impairment. Ablation of Numb in retina significantly impaired visual function. The impaired visual function in Numb deficiency mice is related to the damage of photoreceptors, ion/cation channel activity, synapse formation and phototransduction.
The evolution of early neurogenesis
2015, Developmental Cell
The foundation of the diverse metazoan nervous systems is laid by embryonic patterning mechanisms, involving the generation and movement of neural progenitors and their progeny. Here we divide early neurogenesis into discrete elements, including origin, pattern, proliferation, and movement of neuronal progenitors, which are controlled by conserved gene cassettes. We review these neurogenetic mechanisms in representatives of the different metazoan clades, with the goal to build a conceptual framework in which one can ask specific questions, such as which of these mechanisms potentially formed part of the developmental “toolkit” of the bilaterian ancestor and which evolved later.
Epigenetic programming of hypoxic-ischemic encephalopathy in response to fetal hypoxia
2015, Progress in Neurobiology
Citation Excerpt :
Liu and colleagues found that MBD1 deficiency damaged adult neural stem/progenitor cell (aNSC) differentiation and the neurogenesis process, potentially targeting miR-184 that promotes NSC proliferation and inhibits differentiation. Numbl, a known regulator of the development of the brain and embryonic NSC proliferation and differentiation (Johnson, 2003; Li et al., 2003), is the downstream target of miR-184. Through binding to the 3′UTR of Numbl mRNA, miR184 affects its translation.
Hypoxia is a major stress to the fetal development and may result in irreversible injury in the developing brain, increased risk of central nervous system (CNS) malformations in the neonatal brain and long-term neurological complications in offspring. Current evidence indicates that epigenetic mechanisms may contribute to the development of hypoxic/ischemic-sensitive phenotype in the developing brain in response to fetal stress. However, the causative cellular and molecular mechanisms remain elusive. In the present review, we summarize the recent findings of epigenetic mechanisms in the development of the brain and their roles in fetal hypoxia-induced brain developmental malformations. Specifically, we focus on DNA methylation and active demethylation, histone modifications and microRNAs in the regulation of neuronal and vascular developmental plasticity, which may play a role in fetal stress-induced epigenetic programming of hypoxic/ischemic-sensitive phenotype in the developing brain.
Epigenetic regulation of miR-184 by MBD1 governs neural stem cell proliferation and differentiation
2010, Cell Stem Cell
Citation Excerpt :
We next asked whether Numbl could rescue the deficits associated with miR-184 overexpression. Numbl has been shown to affect the proliferation and differentiation of embryonic NSCs (Johnson, 2003; Li et al., 2003); however, its roles in adult NSCs have not been clearly defined. We therefore tested whether overexpression of Numbl would repress the proliferation of aNSCs.
Methyl-CpG binding protein 1 (MBD1) regulates gene expression via a DNA methylation-mediated epigenetic mechanism. We have previously demonstrated that MBD1 deficiency impairs adult neural stem/progenitor cell (aNSC) differentiation and neurogenesis, but the underlying mechanism was unclear. Here, we show that MBD1 regulates the expression of several microRNAs in aNSCs and, specifically, that miR-184 is directly repressed by MBD1. High levels of miR-184 promoted proliferation but inhibited differentiation of aNSCs, whereas inhibition of miR-184 rescued the phenotypes associated with MBD1 deficiency. We further found that miR-184 regulates the expression of Numblike (Numbl), a known regulator of brain development, by binding to the 3′-UTR of Numbl mRNA and affecting its translation. Expression of exogenous Numbl could rescue the aNSC defects that result from either miR-184 overexpression or MBD1 deficiency. Therefore, MBD1, miR-184, and Numbl form a regulatory network that helps control the balance between proliferation and differentiation of aNSCs.
Mutation and copy number analysis of LNX1 and Numbl in nervous system tumors
2008, Cancer Genetics and Cytogenetics
Citation Excerpt :
Numbl is involved in maintaining neural progenitor cells during embryogenesis by allowing their progenies to choose progenitor over neuronal fate [9]. In addition, Numbl functions to maintain the self-renewal properties of the neural progenitor cells in the neural tube [16]. A recent report shows that mammalian Numb homologs are required throughout neurogenesis to maintain progenitor cells instead of promoting neuronal fates, because Numb and Numbl loss causes premature depletion of progenitor cells and overproduction of neurons [9,10].
Alterations at chromosome locus 4q12 are frequently found in gliomas; this locus contains the receptor tyrosine kinase–encoding genes KIT, PDGFRA, and KDR (alias VEGFR2). Notable among the genes at this locus is LNX1, the ligand of Numb protein X. LNX1 encodes a PDZ domain containing protein, which interacts with the cell fate determinant Numbl, a Numb homolog-like gene involved in the maintenance of neural progenitor cells during embryonic neurogenesis. We performed a mutation analysis for LNX1 and Numbl genes. In addition, gene copy numbers of LNX1, Numbl, and KIT in human nervous system tumors were analyzed by chromogenic in situ hybridization. Tissue samples from 90 patients were screened for LNX1 and Numbl mutations, and tissue sections from 56 samples were analyzed for gene amplification status. Our analysis revealed missense mutations in LNX1 exons 3 and 5 and a single-nucleotide polymorphism in Numbl exon 6. In addition, polyglutamine repeat polymorphism was found in Numbl exon 10. Chromogenic in situ hybridization showed gene amplification of LNX1 in 10%, Numbl in 5%, and KIT in 6% of nervous system tumors. Both gene sequence alterations and amplifications of LNX1 and Numbl are present in a subset of human gliomas, and the role of these genes in neurogenesis suggests that they may contribute to development of glial tumors.
A comparative analysis of leucine-rich repeat kinase 2 (Lrrk2) expression in mouse brain and Lewy body disease
2007, Neuroscience
Citation Excerpt :
A second, weaker Lrrk2 substrate identified by the same authors, collapsin response mediator protein-2 (CRMP-2), is also of interest since CRMP-2 is involved in regulation of growth cones and microtubule dynamics (Stenmark et al., 2007). In addition it also interacts with Numb, an endocytosis-related protein that controls cell number in neurogenesis (Johnson, 2003; Stenmark et al., 2007). Furthermore CRMP-2 is found in active neurogenesis areas including hippocampus and the olfactory bulb (Charrier et al., 2003; Veyrac et al., 2005) Finally, phosphorylated CRMP-2 has been postulated to play a role in neurodegeneration since it is found in neurofibrillary tangles in Alzheimer’s disease (Gu et al., 2000; Yoshida et al., 1998).
Pathogenic substitutions in leucine-rich repeat kinase 2 (LRRK2, Lrrk2) have been genetically linked to familial, late-onset Parkinsonism. End-stage disease is predominantly associated with nigral neuronal loss and Lewy body pathology, but patients may have gliosis, tau or ubiquitin inclusions (pleomorphic pathology). The anatomical distribution of Lrrk2 protein may provide insight into its function in health and neurodegeneration, thus we performed a comparative study with ‘in-house’ and commercially available Lrrk2 antibodies using brain tissue from wild type and human Lrrk2 transgenic bacterial artificial chromosome (BAC) mice, and from diffuse Lewy body disease (DLBD) patients. Lrrk2 protein was ubiquitously expressed and relatively abundant in most brain regions, including the substantia nigra, thalamus and striatum. Lrrk2 was not a major component of Lewy body or neuritic pathology associated with Parkinson’s disease. However, selective loss of dopaminergic neurons in Lrrk2-associated Parkinsonism argues the protein may have regional-specific interactions. Lrrk2 immunohistochemical staining was present in the subventricular zone, a region containing stem cells that give rise to both neurons and glia. A role for Lrrk2 in neurogenesis might provide further insight into the aberrant role of mutant protein in age-associated neurodegeneration with pleomorphic pathology.

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Trends in Neurosciences

Research FocusNumb and Numblike control cell number during vertebrate neurogenesis

Abstract

Section snippets

Opposing roles suggested for Numb in neural development

A role for Numb and Nbl in maintaining the progenitor state

Unresolved issues

Neuron

Trends Neurosci.

Neuron

Neuron

Curr. Biol.

Neuron

Dev. Biol.

Curr. Biol.

Research Focus
Numb and Numblike control cell number during vertebrate neurogenesis