title: Doublecortin-Like Kinases Promote Neuronal Survival and Induce Growth Cone Reformation via Distinct Mechanisms.
abstract: After axotomy, neuronal survival and growth cone re-formation are required for axon regeneration. We discovered that doublecortin-like kinases (DCLKs), members of the doublecortin (DCX) family expressed in adult retinal ganglion cells (RGCs), play critical roles in both processes, through distinct mechanisms. Overexpression of DCLK2 accelerated growth cone re-formation in vitro and enhanced the initiation and elongation of axon re-growth after optic nerve injury. These effects depended on both the microtubule (MT)-binding domain and the serine-proline-rich (S/P-rich) region of DCXs in-cis in the same molecules. While the MT-binding domain is known to stabilize MT structures, we show that the S/P-rich region prevents F-actin destabilization in injured axon stumps. Additionally, while DCXs synergize with mTOR to stimulate axon regeneration, alone they can promote neuronal survival possibly by regulating the retrograde propagation of injury signals. Multifunctional DCXs thus represent potential targets for promoting both survival and regeneration of injured neurons.
authors.affiliation: F.M. Kirby Neurobiology Center, Children's Hospital, and Department of Neurology, Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115, USA.
authors.forename: Homaira
authors.initials: H
authors.lastname: Nawabi
authors.affiliation: F.M. Kirby Neurobiology Center, Children's Hospital, and Department of Neurology, Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115, USA.
authors.forename: Stephane
authors.initials: S
authors.lastname: Belin
authors.affiliation: F.M. Kirby Neurobiology Center, Children's Hospital, and Department of Neurology, Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115, USA.
authors.forename: Romain
authors.initials: R
authors.lastname: Cartoni
authors.affiliation: F.M. Kirby Neurobiology Center, Children's Hospital, and Department of Neurology, Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115, USA.
authors.forename: Philip R
authors.initials: PR
authors.lastname: Williams
authors.affiliation: F.M. Kirby Neurobiology Center, Children's Hospital, and Department of Neurology, Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115, USA.
authors.forename: Chen
authors.initials: C
authors.lastname: Wang
authors.affiliation: F.M. Kirby Neurobiology Center, Children's Hospital, and Department of Neurology, Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115, USA.
authors.forename: Alban
authors.initials: A
authors.lastname: Latremolière
authors.affiliation: F.M. Kirby Neurobiology Center, Children's Hospital, and Department of Neurology, Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115, USA.
authors.forename: Xuhua
authors.initials: X
authors.lastname: Wang
authors.affiliation: F.M. Kirby Neurobiology Center, Children's Hospital, and Department of Neurology, Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115, USA; Jiangsu Key Laboratory of Neuroregeneration, Co-innovation Center of Neuroregeneration, Nantong University, Nantong, 226001, China.
authors.forename: Junjie
authors.initials: J
authors.lastname: Zhu
authors.affiliation: Departments of Physiology and Biophysics, Boston University School of Medicine, Boston, MA 02118, USA.
authors.forename: Daniel G
authors.initials: DG
authors.lastname: Taub
authors.affiliation: Center for Neuroscience Research, Children's National Medical Center, Washington, DC 20010, USA.
authors.forename: Xiaoqin
authors.initials: X
authors.lastname: Fu
authors.affiliation: F.M. Kirby Neurobiology Center, Children's Hospital, and Department of Neurology, Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115, USA; Jiangsu Key Laboratory of Neuroregeneration, Co-innovation Center of Neuroregeneration, Nantong University, Nantong, 226001, China.
authors.forename: Bin
authors.initials: B
authors.lastname: Yu
authors.affiliation: Jiangsu Key Laboratory of Neuroregeneration, Co-innovation Center of Neuroregeneration, Nantong University, Nantong, 226001, China.
authors.forename: Xiaosong
authors.initials: X
authors.lastname: Gu
authors.affiliation: F.M. Kirby Neurobiology Center, Children's Hospital, and Department of Neurology, Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115, USA.
authors.forename: Clifford J
authors.initials: CJ
authors.lastname: Woolf
authors.affiliation: Center for Neuroscience Research, Children's National Medical Center, Washington, DC 20010, USA.
authors.forename: Judy S
authors.initials: JS
authors.lastname: Liu
authors.affiliation: Departments of Physiology and Biophysics, Boston University School of Medicine, Boston, MA 02118, USA.
authors.forename: Christopher V
authors.initials: CV
authors.lastname: Gabel
authors.affiliation: F.M. Kirby Neurobiology Center, Children's Hospital, and Department of Neurology, Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115, USA. Electronic address: judith.steen@childrens.harvard.edu.
authors.forename: Judith A
authors.initials: JA
authors.lastname: Steen
authors.affiliation: F.M. Kirby Neurobiology Center, Children's Hospital, and Department of Neurology, Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115, USA. Electronic address: zhigang.he@childrens.harvard.edu.
authors.forename: Zhigang
authors.initials: Z
authors.lastname: He
mesh_terms: D000199:Actins / Q000378:metabolism*; D000818:Animals; D001369:Axons / Q000378:metabolism* / Q000502:physiology; D019771:Axotomy; D002470:Cell Survival; D000089662:Doublecortin Protein; D000089742:Doublecortin-Like Kinases; D020439:Growth Cones; D066298:In Vitro Techniques; D051379:Mice; D008870:Microtubules / Q000378:metabolism*; D009416:Nerve Regeneration / Q000235:genetics* / Q000502:physiology; D009474:Neurons / Q000378:metabolism / Q000502:physiology; D020221:Optic Nerve Injuries; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism; D012165:Retinal Ganglion Cells / Q000378:metabolism* / Q000502:physiology; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
chemical_list: D000199:Actins; C000714847:Dcx protein, mouse; D000089662:Doublecortin Protein; C546843:mTOR protein, mouse; D000089742:Doublecortin-Like Kinases; C485525:Dclk1 protein, mouse; C540863:Dclk2 protein, mouse; D017346:Protein Serine-Threonine Kinases; D058570:TOR Serine-Threonine Kinases