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Gene Review

Numb  -  numb gene homolog (Drosophila)

Mus musculus

Synonyms: Protein numb homolog, m-Nb, m-Numb, m-numb
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Disease relevance of Numb

  • Drosophila neuroblast 7-3 cell lineage: a model system for studying programmed cell death, Notch/Numb signaling, and sequential specification of ganglion mother cell identity [1].
  • At the stage of endocrine and exocrine divergence, mNumb PRRS continued to be expressed in endocrine lineage cells, whereas PRRL was down-regulated during endocrine differentiation [2].

High impact information on Numb

  • This resulted in severe damage to brain lateral ventricle integrity and identified roles for Numb/Numblike in regulating ependymal wall integrity and SVZ neuroblast survival [3].
  • Our findings show that a shared molecular mechanism, with mouse Numb and Nbl as key components, governs the self-renewal of all neural progenitor cells, regardless of their lineage or regional identities [4].
  • Mouse Numb homologs antagonize Notch1 signaling pathways through largely unknown mechanisms [5].
  • Dividing Lgl1(-/-) cells are unable to asymmetrically localize the Notch inhibitor Numb, and the resulting failure of asymmetric cell divisions may be responsible for the hyperproliferation and the lack of differentiation [6].
  • Continuing role for mouse Numb and Numbl in maintaining progenitor cells during cortical neurogenesis [7].

Biological context of Numb

  • Because progenitor cells can proliferate without Numb and Numbl before neurogenesis, we propose that Numb-mediated asymmetric cell divisions, which diversify many cell fates in Drosophila melanogaster, represent a general mechanism in mammals for stem cells to balance self-renewal and differentiation [7].
  • However, thymocyte development, cell cycle, and survival were unperturbed by mNumb overexpression, even though transgenic Numb was expressed at an early stage in thymocyte development (CD4(-)CD8(-)CD3(-) cells that were CD44(+)CD25(+) or CD44(-)CD25(+); double-negative 2/3) [8].
  • When expressed in Drosophila embryos, m-Numb is localized asymmetrically in dividing neural precursors and rescues the numb mutant phenotype [9].
  • Inactivation of Numb and Numblike in embryonic dorsal forebrain impairs neurogenesis and disrupts cortical morphogenesis [10].
  • Furthermore, we demonstrate that the asymmetric cell-fate determinant Numb segregates selectively to one daughter cell during mitosis and before differentiation, suggesting that Numb is associated with self-renewal [11].

Anatomical context of Numb


Associations of Numb with chemical compounds

  • The adapter protein Numb is a well-characterized inhibitor of Notch and also contains a phosphotyrosine binding domain, suggesting that Numb could provide a link between these pathways [13].
  • In addition, differentiation of P19 cells with retinoic acid leads to the specific loss of expression of the 71- and 72-kDa Numb proteins, suggesting that the expression of certain forms of Numb protein is regulated in a cell type-specific manner [15].
  • Mutational analysis of LNX and peptide competition experiments showed that phosphorylation of the tyrosine residue within this motif was not required for binding to the Numb PTB domain [16].
  • We now report that Numb isoforms containing a short PTB domain increase the vulnerability of PC12 cells to death induced by Abeta1-42 and by 4-hydroxynonenal, a lipid peroxidation product previously shown to mediate neurotoxic effects of Abeta [17].

Regulatory relationships of Numb

  • Furthermore, higher levels of Numb were detected in the cortex of mice expressing mutant amyloid precursor protein (APP) relative to age-matched wild-type mice [17].
  • Finally, we show that template DNA cosegregates with Numb in label-retaining cells that express the self-renewal marker Pax7 [11].
  • The restricted requirement of Numb during neural development in the mouse suggests that in some neuronal lineages, Notch signaling may be regulated independently of Numb [18].

Other interactions of Numb

  • We have also found that, in dividing cortical progenitors, Notch1 is distributed around the entire membrane, unlike m-Numb which is asymmetrically localized to the apical membrane [12].
  • During mouse cortical neurogenesis, m-Numb is asymmetrically localized to the apical membrane of dividing ventricular neural progenitors [9].
  • Cell fate determinants Numb, Notch-1, Shh and BMPs are abundantly expressed during development but mostly decline in the adult [19].
  • Asymmetric Pax6 distribution in neuron pairs was not associated with asymmetric distribution of Numb, which raises an intriguing possibility, that Pax6 asymmetry in neuron pairs is produced by an alternative mode of the cell autonomous mechanisms [20].
  • Distinct expression patterns of splicing isoforms of mNumb in the endocrine lineage of developing pancreas [2].

Analytical, diagnostic and therapeutic context of Numb


  1. Drosophila neuroblast 7-3 cell lineage: a model system for studying programmed cell death, Notch/Numb signaling, and sequential specification of ganglion mother cell identity. Karcavich, R., Doe, C.Q. J. Comp. Neurol. (2005) [Pubmed]
  2. Distinct expression patterns of splicing isoforms of mNumb in the endocrine lineage of developing pancreas. Yoshida, T., Tokunaga, A., Nakao, K., Okano, H. Differentiation (2003) [Pubmed]
  3. Postnatal deletion of numb/numblike reveals repair and remodeling capacity in the subventricular neurogenic niche. Kuo, C.T., Mirzadeh, Z., Soriano-Navarro, M., Rasin, M., Wang, D., Shen, J., Sestan, N., Garcia-Verdugo, J., Alvarez-Buylla, A., Jan, L.Y., Jan, Y.N. Cell (2006) [Pubmed]
  4. Progenitor cell maintenance requires numb and numblike during mouse neurogenesis. Petersen, P.H., Zou, K., Hwang, J.K., Jan, Y.N., Zhong, W. Nature (2002) [Pubmed]
  5. Targeted deletion of numb and numblike in sensory neurons reveals their essential functions in axon arborization. Huang, E.J., Li, H., Tang, A.A., Wiggins, A.K., Neve, R.L., Zhong, W., Jan, L.Y., Jan, Y.N. Genes Dev. (2005) [Pubmed]
  6. Loss of cell polarity causes severe brain dysplasia in Lgl1 knockout mice. Klezovitch, O., Fernandez, T.E., Tapscott, S.J., Vasioukhin, V. Genes Dev. (2004) [Pubmed]
  7. Continuing role for mouse Numb and Numbl in maintaining progenitor cells during cortical neurogenesis. Petersen, P.H., Zou, K., Krauss, S., Zhong, W. Nat. Neurosci. (2004) [Pubmed]
  8. Transgenic expression of numb inhibits notch signaling in immature thymocytes but does not alter T cell fate specification. French, M.B., Koch, U., Shaye, R.E., McGill, M.A., Dho, S.E., Guidos, C.J., McGlade, C.J. J. Immunol. (2002) [Pubmed]
  9. Asymmetric localization of a mammalian numb homolog during mouse cortical neurogenesis. Zhong, W., Feder, J.N., Jiang, M.M., Jan, L.Y., Jan, Y.N. Neuron (1996) [Pubmed]
  10. Inactivation of Numb and Numblike in embryonic dorsal forebrain impairs neurogenesis and disrupts cortical morphogenesis. Li, H.S., Wang, D., Shen, Q., Schonemann, M.D., Gorski, J.A., Jones, K.R., Temple, S., Jan, L.Y., Jan, Y.N. Neuron (2003) [Pubmed]
  11. Asymmetric division and cosegregation of template DNA strands in adult muscle satellite cells. Shinin, V., Gayraud-Morel, B., Gomès, D., Tajbakhsh, S. Nat. Cell Biol. (2006) [Pubmed]
  12. Differential expression of mammalian Numb, Numblike and Notch1 suggests distinct roles during mouse cortical neurogenesis. Zhong, W., Jiang, M.M., Weinmaster, G., Jan, L.Y., Jan, Y.N. Development (1997) [Pubmed]
  13. The Notch regulator Numb links the Notch and TCR signaling pathways. Anderson, A.C., Kitchens, E.A., Chan, S.W., St Hill, C., Jan, Y.N., Zhong, W., Robey, E.A. J. Immunol. (2005) [Pubmed]
  14. Phosphorylation by Rho kinase regulates CRMP-2 activity in growth cones. Arimura, N., Ménager, C., Kawano, Y., Yoshimura, T., Kawabata, S., Hattori, A., Fukata, Y., Amano, M., Goshima, Y., Inagaki, M., Morone, N., Usukura, J., Kaibuchi, K. Mol. Cell. Biol. (2005) [Pubmed]
  15. Characterization of four mammalian numb protein isoforms. Identification of cytoplasmic and membrane-associated variants of the phosphotyrosine binding domain. Dho, S.E., French, M.B., Woods, S.A., McGlade, C.J. J. Biol. Chem. (1999) [Pubmed]
  16. The mammalian numb phosphotyrosine-binding domain. Characterization of binding specificity and identification of a novel PDZ domain-containing numb binding protein, LNX. Dho, S.E., Jacob, S., Wolting, C.D., French, M.B., Rohrschneider, L.R., McGlade, C.J. J. Biol. Chem. (1998) [Pubmed]
  17. Numb modifies neuronal vulnerability to amyloid beta-peptide in an isoform-specific manner by a mechanism involving altered calcium homeostasis: implications for neuronal death in Alzheimer's disease. Chan, S.L., Pedersen, W.A., Zhu, H., Mattson, M.P. Neuromolecular Med. (2002) [Pubmed]
  18. Multiple roles of mouse Numb in tuning developmental cell fates. Zilian, O., Saner, C., Hagedorn, L., Lee, H.Y., Säuberli, E., Suter, U., Sommer, L., Aguet, M. Curr. Biol. (2001) [Pubmed]
  19. Differential expression of cell fate determinants in neurons and glial cells of adult mouse spinal cord after compression injury. Chen, J., Leong, S.Y., Schachner, M. Eur. J. Neurosci. (2005) [Pubmed]
  20. Differential expression of Pax6 and Ngn2 between pair-generated cortical neurons. Kawaguchi, A., Ogawa, M., Saito, K., Matsuzaki, F., Okano, H., Miyata, T. J. Neurosci. Res. (2004) [Pubmed]
  21. Role of glial cell line-derived neurotrophic factor in germ-line stem cell fate. Braydich-Stolle, L., Nolan, C., Dym, M., Hofmann, M.C. Ann. N. Y. Acad. Sci. (2005) [Pubmed]
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