title: Cell Junction Pathology of Neural Stem Cells Is Associated With Ventricular Zone Disruption, Hydrocephalus, and Abnormal Neurogenesis.
abstract: Fetal-onset hydrocephalus affects 1 to 3 per 1,000 live births. It is not only a disorder of cerebrospinal fluid dynamics but also a brain disorder that corrective surgery does not ameliorate. We hypothesized that cell junction abnormalities of neural stem cells (NSCs) lead to the inseparable phenomena of fetal-onset hydrocephalus and abnormal neurogenesis. We used bromodeoxyuridine labeling, immunocytochemistry, electron microscopy, and cell culture to study the telencephalon of hydrocephalic HTx rats and correlated our findings with those in human hydrocephalic and nonhydrocephalic human fetal brains (n = 12 each). Our results suggest that abnormal expression of the intercellular junction proteins N-cadherin and connexin-43 in NSC leads to 1) disruption of the ventricular and subventricular zones, loss of NSCs and neural progenitor cells; and 2) abnormalities in neurogenesis such as periventricular heterotopias and abnormal neuroblast migration. In HTx rats, the disrupted NSC and progenitor cells are shed into the cerebrospinal fluid and can be grown into neurospheres that display intercellular junction abnormalities similar to those of NSC of the disrupted ventricular zone; nevertheless, they maintain their potential for differentiating into neurons and glia. These NSCs can be used to investigate cellular and molecular mechanisms underlying this condition, thereby opening the avenue for stem cell therapy.
authors.affiliation: From the Instituto de Anatomía, Histología y Patología (MMG, RH, AO, NL, KV, CG, MCJ, FH, SR, MJ, EMR), Instituto de Neurociencias Clínicas (EO), Instituto de Obstetricia y Ginecología (FG), Universidad Austral de Chile, Valdivia, Chile; Facultad de Recursos Naturales (AO), Escuela de Medicina Veterinaria, Universidad Católica de Temuco, Araucania, Chile; Departments of Pediatric Neurology and Pediatrics (DAS), and Pathology and Medical Biology (WFAdD), University Medical Center, University of Groningen, Groningen, The Netherlands; Departamento de Biología Celular, Facultad de Ciencias, Universidad de Málaga, Málaga, Spain (AJJ, MDD-P, JMP-F); Department of Neurosurgery, Pediatric Neurosurgery Division, University of Utah, Salt Lake City, Utah (JPMA); and Department of Neurosurgery, Alpert Medical School at Brown University, Providence, Rhode Island (CEJ).
authors.forename: María Montserrat
authors.initials: MM
authors.lastname: Guerra
authors.forename: Roberto
authors.initials: R
authors.lastname: Henzi
authors.forename: Alexander
authors.initials: A
authors.lastname: Ortloff
authors.forename: Nicole
authors.initials: N
authors.lastname: Lichtin
authors.forename: Karin
authors.initials: K
authors.lastname: Vío
authors.forename: Antonio J
authors.initials: AJ
authors.lastname: Jiménez
authors.forename: María Dolores
authors.initials: MD
authors.lastname: Dominguez-Pinos
authors.forename: César
authors.initials: C
authors.lastname: González
authors.forename: Maria Clara
authors.initials: MC
authors.lastname: Jara
authors.forename: Fernando
authors.initials: F
authors.lastname: Hinostroza
authors.forename: Sara
authors.initials: S
authors.lastname: Rodríguez
authors.forename: Maryoris
authors.initials: M
authors.lastname: Jara
authors.forename: Eduardo
authors.initials: E
authors.lastname: Ortega
authors.forename: Francisco
authors.initials: F
authors.lastname: Guerra
authors.forename: Deborah A
authors.initials: DA
authors.lastname: Sival
authors.forename: Wilfred F A
authors.initials: WF
authors.lastname: den Dunnen
authors.forename: José M
authors.initials: JM
authors.lastname: Pérez-Fígares
authors.forename: James P
authors.initials: JP
authors.lastname: McAllister
authors.forename: Conrad E
authors.initials: CE
authors.lastname: Johanson
authors.forename: Esteban M
authors.initials: EM
authors.lastname: Rodríguez
mesh_terms: D000367:Age Factors; D000818:Animals; D000831:Animals, Newborn; D002454:Cell Differentiation; D002465:Cell Movement; D002478:Cells, Cultured; D004622:Embryo, Mammalian; D005260:Female; D005333:Fetus; D005865:Gestational Age; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006801:Humans; D006849:Hydrocephalus / Q000473:pathology*; D007365:Intercellular Junctions / Q000473:pathology* / Q000648:ultrastructure; D008297:Male; D008854:Microscopy, Electron; D058953:Neural Stem Cells / Q000473:pathology* / Q000648:ultrastructure; D055495:Neurogenesis / Q000502:physiology*; D051381:Rats; D013687:Telencephalon / Q000196:embryology / Q000254:growth & development / Q000473:pathology / Q000648:ultrastructure; D014694:Ventricular Outflow Obstruction / Q000473:pathology*
chemical_list: D005904:Glial Fibrillary Acidic Protein