Leibniz Institute on Aging—Fritz Lipmann Institute, Beutenbergstrasse, Germany
Torsten Kroll
Leibniz Institute on Aging—Fritz Lipmann Institute, Beutenbergstrasse, Germany
Amanda M Li
Department of Paediatrics, University of British Columbia, Vancouver, Canada
Daniel Goldowitz
Centre for Molecular Medicine and Therapeutics, University of British Columbia, Vancouver, Canada; Department of Medical Genetics, University of British Columbia, Vancouver, Canada
Lucien Frappart
Leibniz Institute on Aging—Fritz Lipmann Institute, Beutenbergstrasse, Germany
Aspasia Ploubidou
Leibniz Institute on Aging—Fritz Lipmann Institute, Beutenbergstrasse, Germany
Millan S Patel
Department of Medical Genetics, University of British Columbia, Vancouver, Canada
Linda M Pilarski
Cross Cancer Institute, Department of Oncology, University of Alberta, Edmonton, Canada
Elizabeth M Simpson
Centre for Molecular Medicine and Therapeutics, University of British Columbia, Vancouver, Canada; Department of Medical Genetics, University of British Columbia, Vancouver, Canada
Philipp F Lange
Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, Canada; Michael Cuccione Childhood Cancer Research Program, BC Children’s Hospital, Vancouver, Canada
Douglas W Allan
Department of Cellular and Physiological Sciences, Life Sciences Centre, University of British Columbia, Vancouver, Canada
Department of Paediatrics, University of British Columbia, Vancouver, Canada; Michael Cuccione Childhood Cancer Research Program, BC Children’s Hospital, Vancouver, Canada
Oriented cell division is one mechanism progenitor cells use during development and to maintain tissue homeostasis. Common to most cell types is the asymmetric establishment and regulation of cortical NuMA-dynein complexes that position the mitotic spindle. Here, we discover that HMMR acts at centrosomes in a PLK1-dependent pathway that locates active Ran and modulates the cortical localization of NuMA-dynein complexes to correct mispositioned spindles. This pathway was discovered through the creation and analysis of Hmmr-knockout mice, which suffer neonatal lethality with defective neural development and pleiotropic phenotypes in multiple tissues. HMMR over-expression in immortalized cancer cells induces phenotypes consistent with an increase in active Ran including defects in spindle orientation. These data identify an essential role for HMMR in the PLK1-dependent regulatory pathway that orients progenitor cell division and supports neural development.
