Loss of Wwox Causes Defective Development of Cerebral Cortex with Hypomyelination in a Rat Model of Lethal Dwarfism with Epilepsy

Int J Mol Sci. 2019 Jul 23;20(14):3596. doi: 10.3390/ijms20143596.

Abstract

WW domain-containing oxidoreductase (Wwox) is a putative tumor suppressor. Several germline mutations of Wwox have been associated with infant neurological disorders characterized by epilepsy, growth retardation, and early death. Less is known, however, about the pathological link between Wwox mutations and these disorders or the physiological role of Wwox in brain development. In this study, we examined age-related expression and histological localization of Wwox in forebrains as well as the effects of loss of function mutations in the Wwox gene in the immature cortex of a rat model of lethal dwarfism with epilepsy (lde/lde). Immunostaining revealed that Wwox is expressed in neurons, astrocytes, and oligodendrocytes. lde/lde cortices were characterized by a reduction in neurite growth without a reduced number of neurons, severe reduction in myelination with a reduced number of mature oligodendrocytes, and a reduction in cell populations of astrocytes and microglia. These results indicate that Wwox is essential for normal development of neurons and glial cells in the cerebral cortex.

Keywords: Wwox; cerebral cortex; neuron; oligodendrocyte.

MeSH terms

  • 2',3'-Cyclic Nucleotide 3'-Phosphodiesterase / genetics
  • 2',3'-Cyclic Nucleotide 3'-Phosphodiesterase / metabolism
  • Adenomatous Polyposis Coli Protein / genetics
  • Adenomatous Polyposis Coli Protein / metabolism
  • Amino Acid Transport Systems, Acidic / deficiency*
  • Amino Acid Transport Systems, Acidic / genetics
  • Amino Acid Transport Systems, Acidic / metabolism
  • Animals
  • Antiporters / deficiency*
  • Antiporters / genetics
  • Antiporters / metabolism
  • Astrocytes / metabolism
  • Astrocytes / pathology
  • Cell Count
  • Cerebral Cortex / growth & development
  • Cerebral Cortex / metabolism*
  • Cerebral Cortex / pathology
  • Disease Models, Animal
  • Dwarfism / genetics*
  • Dwarfism / metabolism
  • Dwarfism / pathology
  • Epilepsy / genetics*
  • Epilepsy / metabolism
  • Epilepsy / pathology
  • Gene Expression Regulation, Developmental
  • Germ-Line Mutation
  • Glial Fibrillary Acidic Protein / genetics
  • Glial Fibrillary Acidic Protein / metabolism
  • Hereditary Central Nervous System Demyelinating Diseases / genetics*
  • Hereditary Central Nervous System Demyelinating Diseases / metabolism
  • Hereditary Central Nervous System Demyelinating Diseases / pathology
  • Male
  • Mitochondrial Diseases / genetics*
  • Mitochondrial Diseases / metabolism
  • Mitochondrial Diseases / pathology
  • Myelin Basic Protein / genetics
  • Myelin Basic Protein / metabolism
  • Neurogenesis / genetics*
  • Neurons / metabolism
  • Neurons / pathology
  • Oligodendroglia / metabolism
  • Oligodendroglia / pathology
  • Prosencephalon / growth & development
  • Prosencephalon / metabolism
  • Prosencephalon / pathology
  • Psychomotor Disorders / genetics*
  • Psychomotor Disorders / metabolism
  • Psychomotor Disorders / pathology
  • Rats
  • Rats, Transgenic
  • Signal Transduction
  • Tumor Suppressor Proteins / deficiency
  • Tumor Suppressor Proteins / genetics*
  • WW Domain-Containing Oxidoreductase / deficiency
  • WW Domain-Containing Oxidoreductase / genetics*

Substances

  • Adenomatous Polyposis Coli Protein
  • Amino Acid Transport Systems, Acidic
  • Antiporters
  • GFAP protein, rat
  • Glial Fibrillary Acidic Protein
  • Mbp protein, rat
  • Myelin Basic Protein
  • Tumor Suppressor Proteins
  • WW Domain-Containing Oxidoreductase
  • WWOX protein, rat
  • 2',3'-Cyclic Nucleotide 3'-Phosphodiesterase
  • Cnp protein, rat

Supplementary concepts

  • Hypomyelination, Global Cerebral