Cell necrosis, intrinsic apoptosis and senescence contribute to the progression of exencephaly to anencephaly in a mice model of congenital chranioschisis
| Autor: | Aimen F. Shaaban, Federico Scorletti, Rebeca Lopes Figueira, Jose L. Peiro, Alejandra Fernandez-Martin, Mario Marotta, Irati Fernandez-Alonso, Lourenço Sbragia, Lucas E Turner, Soner Duru, Marc Oria |
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| Přispěvatelé: | [Oria M, Duru S, Fernandez-Alonso I] Center for Fetal and Placental Research, Cincinnati Children's Hospital Medical Center (CCHMC), Cincinnati, USA. [Figueira RL] Center for Fetal and Placental Research, Cincinnati Children's Hospital Medical Center (CCHMC), Cincinnati, USA. Laboratory of Experimental Fetal Surgery 'Michael Harrison', Division of Pediatric Surgery, Department of Surgery and Anatomy, Ribeirao Preto Medical School, University of Sao Paulo-USP, Ribeirao Preto, Brazil. [Scorletti F] Center for Fetal and Placental Research, Cincinnati Children's Hospital Medical Center (CCHMC), Cincinnati, USA. Department of Pediatric Surgery, Hospital Bambino Gesu, Rome, Italy. [Turner LE] The Chicago Institute for Fetal Health, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, USA. Department of Pediatric Surgery, Northwestern University, Feinberg School of Medicine, Chicago, USA. [Fernandez-Martin A, Marotta M] Center for Fetal and Placental Research, Cincinnati Children's Hospital Medical Center (CCHMC), Cincinnati, USA. Laboratori de Bioenginyeria, Teràpia Cel•lular i Cirurgia en Malformacions Congènites, Vall d'Hebron Institut de Recerca (VHIR), Barcelona, Spain. Universitat Autònoma de Barcelona, Barcelona, Spain, Vall d'Hebron Barcelona Hospital Campus |
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Cancer Research Pathology estructuras embrionarias::feto::líquido amniótico [ANATOMÍA] Embryonic Structures::Fetus::Amniotic Fluid [ANATOMY] ANENCEFALIA Hippocampus Apoptosis Congenital Hereditary and Neonatal Diseases and Abnormalities::Congenital Abnormalities::Nervous System Malformations [DISEASES] Exencephaly Mice 0302 clinical medicine Fetus - Cervell - Malformacions Neural Tube Defects Neural tube defects Cellular Senescence Rates (Animals de laboratori) Neurons Neural tube defect Caspase 3 lcsh:Cytology Brain Caspase 9 Up-Regulation medicine.anatomical_structure Spinal Cord Disease Progression Female Microglia Cyclin-Dependent Kinase Inhibitor p21 Senescence medicine.medical_specialty mortality Immunology Biology Article Necrosis 03 medical and health sciences Cellular and Molecular Neuroscience Anencephaly medicine Animals lcsh:QH573-671 Cyclin-Dependent Kinase Inhibitor p16 enfermedades y anomalías neonatales congénitas y hereditarias::anomalías congénitas::malformaciones del sistema nervioso [ENFERMEDADES] Retinoblastoma-Like Protein p130 Disease model Líquid amniòtic Valproic Acid Intrinsic apoptosis Eukaryota::animales::Chordata::vertebrados::mamíferos::Eutheria::Rodentia::Muridae::Murinae::ratones::ratones de cepas mutantes::ratones mutantes neurológicos [ORGANISMOS] Cell Biology Amniotic Fluid Spinal cord medicine.disease Disease Models Animal Eukaryota::Animals::Chordata::Vertebrates::Mammals::Eutheria::Rodentia::Muridae::Murinae::Mice::Mice Mutant Strains::Mice Neurologic Mutants [ORGANISMS] 030104 developmental biology mortalidad biology.protein Tumor Suppressor Protein p53 NeuN 030217 neurology & neurosurgery |
| Zdroj: | Repositório Institucional da USP (Biblioteca Digital da Produção Intelectual) Universidade de São Paulo (USP) instacron:USP Cell Death and Disease, Vol 10, Iss 10, Pp 1-11 (2019) Scientia Cell Death & Disease Dipòsit Digital de Documents de la UAB Universitat Autònoma de Barcelona |
| Popis: | Amniotic fluid; Neonatal mortality; Exencephaly Líquido amniótico; Mortalidad neonatal; Exencefalia Líquid amniòtic; Mortalitat neonatal; Exencefàlia Exencephaly/anencephaly is one of the leading causes of neonatal mortality and the most extreme open neural tube defect with no current treatments and limited mechanistic understanding. We hypothesized that exencephaly leads to a local neurodegenerative process in the brain exposed to the amniotic fluid as well as diffuse degeneration in other encephalic areas and the spinal cord. To evaluate the consequences of in utero neural tissue exposure, brain and spinal cord samples from E17 exencephalic murine fetuses (maternal intraperitoneal administration of valproic acid at E8) were analyzed and compared to controls and saline-injected shams (n = 11/group). Expression of apoptosis and senescence genes (p53, p21, p16, Rbl2, Casp3, Casp9) was determined by qRT-PCR and protein expression analyzed by western blot. Apoptosis was measured by TUNEL assay and PI/AV flow cytometry. Valproic acid at E8 induced exencephaly in 22% of fetuses. At E17 the fetuses exhibited the characteristic absence of cranial bones. The brain structures from exencephalic fetuses demonstrated a loss of layers in cortical regions and a complete loss of structural organization in the olfactory bulb, hippocampus, dental gyrus and septal cortex. E17 fetuses had reduced expression of NeuN, GFAP and Oligodendrocytes in the brain with primed microglia. Intrinsic apoptotic activation (p53, Caspase9 and 3) was upregulated and active Caspase3 localized to the layer of brain exposed to the amniotic fluid. Senescence via p21-Rbl2 was increased in the brain and in the spinal cord at the lamina I-II of the somatosensory dorsal horn. The current study characterizes CNS alterations in murine exencephaly and demonstrates that degeneration due to intrinsic apoptosis and senescence occurs in the directly exposed brain but also remotely in the spinal cord. This work was supported by Prof. Jose L. Peiro internal Cincinnati Children's Hospital funding. |
| Databáze: | OpenAIRE |
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