Huntingtin regulates mammary stem cell division and differentiation

Stem Cell Reports. 2014 Apr 3;2(4):491-506. doi: 10.1016/j.stemcr.2014.02.011. eCollection 2014 Apr 8.

Abstract

Little is known about the mechanisms of mitotic spindle orientation during mammary gland morphogenesis. Here, we report the presence of huntingtin, the protein mutated in Huntington's disease, in mouse mammary basal and luminal cells throughout mammogenesis. Keratin 5-driven depletion of huntingtin results in a decreased pool and specification of basal and luminal progenitors, and altered mammary morphogenesis. Analysis of mitosis in huntingtin-depleted basal progenitors reveals mitotic spindle misorientation. In mammary cell culture, huntingtin regulates spindle orientation in a dynein-dependent manner. Huntingtin is targeted to spindle poles through its interaction with dynein and promotes the accumulation of NUMA and LGN. Huntingtin is also essential for the cortical localization of dynein, dynactin, NUMA, and LGN by regulating their kinesin 1-dependent trafficking along astral microtubules. We thus suggest that huntingtin is a component of the pathway regulating the orientation of mammary stem cell division, with potential implications for their self-renewal and differentiation properties.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Carrier Proteins / metabolism
  • Cell Cycle Proteins
  • Cell Differentiation / genetics*
  • Cell Division / genetics*
  • Cell Line
  • Dynactin Complex
  • Dyneins / metabolism
  • Epithelium / metabolism
  • Female
  • Humans
  • Huntingtin Protein
  • Lactation / genetics
  • Mammary Glands, Animal / cytology*
  • Mammary Glands, Animal / growth & development
  • Membrane Proteins / metabolism
  • Mice
  • Microtubule-Associated Proteins / metabolism
  • Mitosis
  • Morphogenesis
  • Multiprotein Complexes / metabolism
  • Nerve Tissue Proteins / genetics*
  • Nerve Tissue Proteins / metabolism
  • Nuclear Proteins / genetics*
  • Nuclear Proteins / metabolism
  • Pregnancy
  • Protein Binding
  • Protein Transport
  • RNA Interference
  • Spindle Apparatus
  • Stem Cells / cytology*
  • Stem Cells / metabolism*

Substances

  • Carrier Proteins
  • Cell Cycle Proteins
  • Dynactin Complex
  • Htt protein, mouse
  • Huntingtin Protein
  • Ktn1 protein, mouse
  • LGN protein, mouse
  • Membrane Proteins
  • Microtubule-Associated Proteins
  • Multiprotein Complexes
  • Nerve Tissue Proteins
  • Nuclear Proteins
  • Numa1 protein, mouse
  • Dyneins