Distinct functions of human numb isoforms revealed by misexpression in the neural stem cell lineage in the Drosophila larval brain

Masako Toriya, Akinori Tokunaga, Kazunobu Sawamoto, Keiko Nakao, Hideyuki Okano

Research output: Contribution to journalArticle

30 Citations (Scopus)

Abstract

Mammalian Numb (mNumb) has multiple functions and plays important roles in the regulation of neural development, including maintenance of neural progenitor cells and promotion of neuronal differentiation in the central nervous system (CNS). However, the molecular bases underlying the distinct functions of Numb have not yet been elucidated. mNumb, which has four splicing isoforms, can be divided into two types based on the presence or absence of an amino acid insert in the proline-rich region (PRR) in the C-terminus. It has been proposed that the distinct functions of mNumb may be attributable to these two different types of isoforms. In this study, we used the outer optic anlage (OOA) of the Drosophila larval brain as an assay system to analyze the functions of these two types of isoforms in the neural stem cells, since the proliferation pattern of neuroepithelial (NE) stem cells in the OOA closely resembles that of the vertebrate neural stem/progenitor cells. They divide to expand the progenitor cell pool during early neurogenesis and to produce neural precursors/neurons during late neurogenesis. Clonal analysis in the OOA allows one to discriminate between the NE stem cells, which divide symmetrically to expand the progenitor pool, and the postembryonic neuroblasts (pNBs), which divide asymmetrically to produce neural precursors (ganglion mother cells), each of which divides once to produce two neurons. We found that in the OOA, the human Numb isoform with a long PRR domain (hNumb-PRRL), which is mainly expressed during early neurogenesis in the mouse CNS, promotes proliferation of both NE cells and pNBs without affecting neuronal differentiation, while the other type of hNumb isoform with a short PRR domain (hNumb-PRRS), which is expressed throughout neurogenesis in the mouse embryonic CNS, inhibits proliferation of the stem cells and promotes neuronal differentiation. We also found that hNumb-PRRS, a functional homologue of Drosophila Numb, more strongly decreases the amount of nuclear Notch than hNumb-PRRL, and could antagonize Notch functions probably through endocytic degradation, suggesting that the two distinct types of hNumb isoforms could contribute to different phases of neurogenesis in the mouse embryonic CNS.

Original languageEnglish
Pages (from-to)142-155
Number of pages14
JournalDevelopmental Neuroscience
Volume28
Issue number1-2
DOIs
Publication statusPublished - 2006 Feb

Fingerprint

Neural Stem Cells
Cell Lineage
Drosophila
Protein Isoforms
Neurogenesis
Stem Cells
Neuroepithelial Cells
Brain
Central Nervous System
Porcine Reproductive and Respiratory Syndrome
Proline
Neurons
Ganglia
Vertebrates
Maintenance
Cell Proliferation
Amino Acids

Keywords

  • Drosophila
  • Neuronal differentiation
  • Notch signaling
  • Numb
  • Postembryonic neuroblast
  • Stem cell

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Distinct functions of human numb isoforms revealed by misexpression in the neural stem cell lineage in the Drosophila larval brain. / Toriya, Masako; Tokunaga, Akinori; Sawamoto, Kazunobu; Nakao, Keiko; Okano, Hideyuki.

In: Developmental Neuroscience, Vol. 28, No. 1-2, 02.2006, p. 142-155.

Research output: Contribution to journalArticle

Toriya, Masako ; Tokunaga, Akinori ; Sawamoto, Kazunobu ; Nakao, Keiko ; Okano, Hideyuki. / Distinct functions of human numb isoforms revealed by misexpression in the neural stem cell lineage in the Drosophila larval brain. In: Developmental Neuroscience. 2006 ; Vol. 28, No. 1-2. pp. 142-155.
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