title: NuMA-microtubule interactions are critical for spindle orientation and the morphogenesis of diverse epidermal structures.
abstract: Mitotic spindle orientation is used to generate cell fate diversity and drive proper tissue morphogenesis. A complex of NuMA and dynein/dynactin is required for robust spindle orientation in a number of cell types. Previous research proposed that cortical dynein/dynactin was sufficient to generate forces on astral microtubules (MTs) to orient the spindle, with NuMA acting as a passive tether. In this study, we demonstrate that dynein/dynactin is insufficient for spindle orientation establishment in keratinocytes and that NuMA's MT-binding domain, which targets MT tips, is also required. Loss of NuMA-MT interactions in skin caused defects in spindle orientation and epidermal differentiation, leading to neonatal lethality. In addition, we show that NuMA-MT interactions are also required in adult mice for hair follicle morphogenesis and spindle orientation within the transit-amplifying cells of the matrix. Loss of spindle orientation in matrix cells results in defective differentiation of matrix-derived lineages. Our results reveal an additional and direct function of NuMA during mitotic spindle positioning, as well as a reiterative use of spindle orientation in the skin to build diverse structures.
authors.affiliation: Department of Dermatology, Duke University Medical Center, Durham, United States.|Department of Cell Biology, Duke University Medical Center, Durham, United States.
authors.forename: Lindsey
authors.initials: L
authors.lastname: Seldin
authors.affiliation: Department of Dermatology, Duke University Medical Center, Durham, United States.|Department of Cell Biology, Duke University Medical Center, Durham, United States.
authors.forename: Andrew
authors.initials: A
authors.lastname: Muroyama
authors.affiliation: Department of Dermatology, Duke University Medical Center, Durham, United States.|Department of Cell Biology, Duke University Medical Center, Durham, United States.
authors.forename: Terry
authors.identifier: http://orcid.org/0000-0003-3901-7013
authors.initials: T
authors.lastname: Lechler
mesh_terms: D000818:Animals; D018797:Cell Cycle Proteins; D002455:Cell Division; D000072159:Dynactin Complex / Q000378:metabolism; D004398:Dyneins / Q000378:metabolism; D015603:Keratinocytes / Q000502:physiology*; D051379:Mice; D008870:Microtubules / Q000378:metabolism; D009024:Morphogenesis; D009687:Nuclear Proteins / Q000378:metabolism*; D011485:Protein Binding; D012879:Skin Physiological Phenomena; D008941:Spindle Apparatus / Q000378:metabolism*
chemical_list: D018797:Cell Cycle Proteins; D000072159:Dynactin Complex; D009687:Nuclear Proteins; C489080:Numa1 protein, mouse; D004398:Dyneins
keywords: NuMA; asymmetric cell division; cell biology; developmental biology; mouse; skin; spindle orientation; stem cells