Non-canonical Wnt signaling promotes directed migration of intestinal stem cells to sites of injury.

Tissue regeneration after injury requires coordinated regulation of stem cell activation, division, and daughter cell differentiation, processes that are increasingly well understood in many regenerating tissues. How accurate stem cell positioning and localized integration of new cells into the damaged epithelium are achieved, however, remains unclear. Here, we show that enteroendocrine cells coordinate stem cell migration towards a wound in the Drosophila intestinal epithelium. In response to injury, enteroendocrine cells release the N-terminal domain of the PTK7 orthologue, Otk, which activates non-canonical Wnt signaling in intestinal stem cells, promoting actin-based protrusion formation and stem cell migration towards a wound. We find that this migratory behavior is closely linked to proliferation, and that it is required for efficient tissue repair during injury. Our findings highlight the role of non-canonical Wnt signaling in regeneration of the intestinal epithelium, and identify enteroendocrine cell-released ligands as critical coordinators of intestinal stem cell migration.

Control of Intestinal Cell Fate by Dynamic Mitotic Spindle Repositioning Influences Epithelial Homeostasis and Longevity.

Tissue homeostasis depends on precise yet plastic regulation of stem cell daughter fates. During growth, Drosophila intestinal stem cells (ISCs) adjust fates by switching from asymmetric to symmetric lineages to scale the size of the ISC population. Using a combination of long-term live imaging, lineage tracing, and genetic perturbations, we demonstrate that this switch is executed through the control of mitotic spindle orientation by Jun-N-terminal kinase (JNK) signaling. JNK interacts with the WD40-repeat protein Wdr62 at the spindle and transcriptionally represses the kinesin Kif1a to promote planar spindle orientation. In stress conditions, this function becomes deleterious, resulting in overabundance of symmetric fates and contributing to the loss of tissue homeostasis in the aging animal. Restoring normal ISC spindle orientation by perturbing the JNK/Wdr62/Kif1a axis is sufficient to improve intestinal physiology and extend lifespan. Our findings reveal a critical role for the dynamic control of SC spindle orientation in epithelial maintenance.

Emerging roles for motor proteins in progenitor cell behavior and neuronal migration during brain development.

Over the past two decades, substantial progress has been made in visualizing and understanding neuronal cell migration and morphogenesis during brain development. Distinct mechanisms have evolved to support migration of the various cell types that compose the developing neocortex. A specific subset of molecular motors, so far consisting of cytoplasmic dynein 1, Kif1a and myosin II, are responsible for cytoskeletal and nuclear transport in these cells. This review focuses on the emerging roles for each of these motor proteins in the migratory mechanisms of neocortical cell types. We discuss how migration can be cell cycle regulated and how coordination of motor activity is required to ensure migratory direction. © 2016 Wiley Periodicals, Inc.

KIF1A inhibition immortalizes brain stem cells but blocks BDNF-mediated neuronal migration.

Brain neural stem cells (radial glial progenitors, RGPs) undergo a mysterious form of cell cycle-entrained interkinetic nuclear migration (INM) that is driven apically by cytoplasmic dynein and basally by the kinesin KIF1A, which has recently been implicated in human brain developmental disease. To understand the consequences of altered basal INM and the roles of KIF1A in disease, we performed constitutive and conditional RNAi and expressed mutant KIF1A in E16 to P7 rat RGPs and neurons. RGPs inhibited in basal INM still showed normal cell cycle progression, although neurogenic divisions were severely reduced. Postmitotic neuronal migration was independently disrupted at the multipolar stage and accompanied by premature ectopic expression of neuronal differentiation markers. Similar effects were unexpectedly observed throughout the layer of surrounding control cells, mimicked by Bdnf (brain-derived neurotrophic factor) or Dcx RNAi, and rescued by BDNF application. These results identify sequential and independent roles for KIF1A and provide an important new approach for reversing the effects of human disease.

Dynein recruitment to nuclear pores activates apical nuclear migration and mitotic entry in brain progenitor cells.

Radial glial progenitors (RGPs) are elongated epithelial cells that give rise to neurons, glia, and adult stem cells during brain development. RGP nuclei migrate basally during G1, apically using cytoplasmic dynein during G2, and undergo mitosis at the ventricular surface. By live imaging of in utero electroporated rat brain, we find that two distinct G2-specific mechanisms for dynein nuclear pore recruitment are essential for apical nuclear migration. The "RanBP2-BicD2" and "Nup133-CENP-F" pathways act sequentially, with Nup133 or CENP-F RNAi arresting nuclei close to the ventricular surface in a premitotic state. Forced targeting of dynein to the nuclear envelope rescues nuclear migration and cell-cycle progression, demonstrating that apical nuclear migration is not simply correlated with cell-cycle progression from G2 to mitosis, but rather, is a required event. These results reveal that cell-cycle control of apical nuclear migration occurs by motor protein recruitment and identify a role for nucleus- and centrosome-associated forces in mitotic entry. PAPERCLIP: