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Multifunctional protein 4.1R regulates the asymmetric segregation of Numb during terminal erythroid maturation.

Abstract
The asymmetric cell division of stem or progenitor cells generates daughter cells with distinct fates that balance proliferation and differentiation. Asymmetric segregation of Notch signaling regulatory protein Numb plays a crucial role in cell diversification. However, the molecular mechanism remains unclear. Here, we examined the unequal distribution of Numb in the daughter cells of murine erythroleukemia cells (MELCs) that undergo DMSO-induced erythroid differentiation. In contrast to the cytoplasmic localization of Numb during uninduced cell division, Numb is concentrated at the cell boundary in interphase, near the one-spindle pole in metaphase, and is unequally distributed to one daughter cell in anaphase in induced cells. The inheritance of Numb guides this daughter cell toward erythroid differentiation while the other cell remains a progenitor cell. Mitotic spindle orientation, critical for distribution of cell fate determinants, requires complex communication between the spindle microtubules and the cell cortex mediated by the NuMA-LGN-dynein/dynactin complex. Depletion of each individual member of the complex randomizes the position of Numb relative to the mitotic spindle. Gene replacement confirms that multifunctional erythrocyte protein 4.1R (4.1R) functions as a member of the NuMA-LGN-dynein/dynactin complex and is necessary for regulating spindle orientation, in which interaction between 4.1R and NuMA plays an important role. These results suggest that mispositioning of Numb is the result of spindle misorientation. Finally, disruption of the 4.1R-NuMA-LGN complex increases Notch signaling and decreases the erythroblast population. Together, our results identify a critical role for 4.1R in regulating the asymmetric segregation of Numb to mediate erythropoiesis.
AuthorsShu-Ching Huang, Long V Vu, Faye H Yu, Dan T Nguyen, Edward J Benz Jr
JournalThe Journal of biological chemistry (J Biol Chem) Vol. 297 Issue 3 Pg. 101051 (09 2021) ISSN: 1083-351X [Electronic] United States
PMID34364872 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
CopyrightCopyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.
Chemical References
  • Cell Cycle Proteins
  • Dynactin Complex
  • Epb41 protein, mouse
  • LGN protein, mouse
  • Membrane Proteins
  • Microfilament Proteins
  • Nerve Tissue Proteins
  • Numb protein, mouse
  • Protein Isoforms
  • Dyneins
Topics
  • Animals
  • Asymmetric Cell Division
  • Cell Cycle Proteins (genetics, metabolism)
  • Cell Differentiation
  • Cell Line, Tumor
  • Dynactin Complex (genetics, metabolism)
  • Dyneins (genetics, metabolism)
  • Erythroid Cells (cytology, metabolism)
  • Membrane Proteins (genetics, metabolism)
  • Mice
  • Microfilament Proteins (genetics, metabolism)
  • Mitosis
  • Nerve Tissue Proteins (genetics, metabolism)
  • Protein Binding
  • Protein Isoforms (genetics, metabolism)
  • Spindle Apparatus (genetics, metabolism)

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