Ndel1 and Reelin Maintain Postnatal CA1 Hippocampus Integrity.
How the integrity of laminar structures in the postnatal brain is maintained impacts neuronal functions. Ndel1, the mammalian homolog of NuDE from the filamentous fungus Aspergillus nidulans, is an atypical microtubule (MT)-associated protein that was initially investigated in the contexts of neurogenesis and neuronal migration. Constitutive knock-out mice for Ndel1 are embryonic lethal, thereby necessitating the creation a conditional knock-out to probe the roles of Ndel1 in postnatal brains. Here we report that CA1 pyramidal neurons from mice postnatally lacking Ndel1 (Ndel1 conditional knock-out) exhibit fragmented MTs, dendritic/synaptic pathologies, are intrinsically hyperexcitable and undergo dispersion independently of neuronal migration defect. Secondary to the pyramidal cell changes is the decreased inhibitory drive onto pyramidal cells from interneurons. Levels of the glycoprotein Reelin that regulates MTs, neuronal plasticity, and cell compaction are significantly reduced in hippocampus of mutant mice. Strikingly, a single injection of Reelin into the hippocampus of Ndel1 conditional knock-out mice ameliorates ultrastructural, cellular, morphological, and anatomical CA1 defects. Thus, Ndel1 and Reelin contribute to maintain postnatal CA1 integrity.



The significance of this study rests in the elucidation of a role for Nde1l and Reelin in postnatal CA1 integrity using a new conditional knock-out mouse model for the cytoskeletal protein Ndel1, one that circumvents the defects associated with neuronal migration and embryonic lethality. Our study serves as a basis for understanding the mechanisms underlying postnatal hippocampal maintenance and function, and the significance of decreased levels of Ndel1 and Reelin observed in patients with neurological disorders.
Departments of Clinical Neurosciences, Cell Biology and Anatomy, and Biochemistry and Molecular Biology, Hotchkiss Brain Institute, Alberta Children Hospital Research Institute for Child and Maternal Health, University of Calgary, Calgary, Alberta T2N 4N1, Canada.
Yulan
Y
Jiang
Departments of Pediatrics and Clinical Neurosciences, Alberta Children's Hospital Research Institute for Child and Maternal Health, University of Calgary, Calgary, Alberta T2N 4N1, Canada.
Cezar
C
Gavrilovici
Departments of Clinical Neurosciences, Cell Biology and Anatomy, and Biochemistry and Molecular Biology, Hotchkiss Brain Institute, Alberta Children Hospital Research Institute for Child and Maternal Health, University of Calgary, Calgary, Alberta T2N 4N1, Canada.
Mathieu
M
Chansard
Departments of Clinical Neurosciences, Cell Biology and Anatomy, and Biochemistry and Molecular Biology, Hotchkiss Brain Institute, Alberta Children Hospital Research Institute for Child and Maternal Health, University of Calgary, Calgary, Alberta T2N 4N1, Canada.
Rui Han
RH
Liu
Departments of Clinical Neurosciences, Cell Biology and Anatomy, and Biochemistry and Molecular Biology, Hotchkiss Brain Institute, Alberta Children Hospital Research Institute for Child and Maternal Health, University of Calgary, Calgary, Alberta T2N 4N1, Canada.
Ivana
0000-0001-5707-800X
I
Kiroski
Departments of Clinical Neurosciences, Cell Biology and Anatomy, and Biochemistry and Molecular Biology, Hotchkiss Brain Institute, Alberta Children Hospital Research Institute for Child and Maternal Health, University of Calgary, Calgary, Alberta T2N 4N1, Canada.
Kari
K
Parsons
Department of Life Science, Division of Molecular and Life Science, Pohang, University of Science and Technology, Pohang 790-784, Republic of Korea, and.
Sang Ki
SK
Park
Department of Cell Biology and Anatomy, Hotchkiss Brain Institute, Alberta Children Hospital Research Institute for Child and Maternal Health, University of Calgary, Calgary, Alberta T2N 4N1, Canada.
G Campbell
GC
Teskey
Departments of Pediatrics and Clinical Neurosciences, Alberta Children's Hospital Research Institute for Child and Maternal Health, University of Calgary, Calgary, Alberta T2N 4N1, Canada.
Jong M
JM
Rho
Departments of Clinical Neurosciences, Cell Biology and Anatomy, and Biochemistry and Molecular Biology, Hotchkiss Brain Institute, Alberta Children Hospital Research Institute for Child and Maternal Health, University of Calgary, Calgary, Alberta T2N 4N1, Canada, mdnguyen@ucalgary.ca.
Minh Dang
MD
Nguyen
D000367:Age Factors; D000818:Animals; D000831:Animals, Newborn; D056547:CA1 Region, Hippocampal / Q000254:growth & development* / Q000378:metabolism* / Q000648:ultrastructure; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000235:genetics / Q000378:metabolism; D015816:Cell Adhesion Molecules, Neuronal / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D003712:Dendrites / Q000378:metabolism / Q000648:ultrastructure; D016326:Extracellular Matrix Proteins / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D005968:Glutamate Decarboxylase / Q000378:metabolism; D066298:In Vitro Techniques; D008564:Membrane Potentials / Q000187:drug effects / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008869:Microtubule-Associated Proteins; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D018377:Neurotransmitter Agents / Q000494:pharmacology; D000091042:Reelin Protein; D012697:Serine Endopeptidases / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D016622:Silver Staining; D013569:Synapses / Q000378:metabolism / Q000648:ultrastructure
D015816:Cell Adhesion Molecules, Neuronal; D018797:Cell Cycle Proteins; D016326:Extracellular Matrix Proteins; D008869:Microtubule-Associated Proteins; C531336:Nde1 protein, mouse; D009419:Nerve Tissue Proteins; D018377:Neurotransmitter Agents; D000091042:Reelin Protein; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; C000717128:Reln protein, mouse; D012697:Serine Endopeptidases; D005968:Glutamate Decarboxylase; C402565:glutamate decarboxylase 1
cytoskeleton; dendrites; hippocampus; knock-out; microtubules; synapses