title: Apoptosis of Oligodendrocytes during Early Development Delays Myelination and Impairs Subsequent Responses to Demyelination.
abstract: During mammalian development, myelin-forming oligodendrocytes are generated and axons ensheathed according to a tightly regulated sequence of events. Excess premyelinating oligodendrocytes are eliminated by apoptosis and the timing of the onset of myelination in any specific CNS region is highly reproducible. Although the developing CNS recovers more effectively than the adult CNS from similar insults, it is unknown whether early loss of oligodendrocyte lineage cells leads to long-term functional deficits. To directly assess whether the loss of oligodendrocytes during early postnatal spinal cord development impacted oligodendrogenesis, myelination, and remyelination, transgenic mouse lines were generated in which a modified caspase-9 molecule allowed spatial and temporal control of the apoptotic pathway specifically in mature, myelin basic protein expressing oligodendrocytes (MBP-iCP9). Activating apoptosis in MBP(+) cells of the developing spinal cord during the first postnatal week inhibited myelination. This inhibition was transient, and the levels of myelination largely returned to normal after 2 weeks. Despite robust developmental plasticity, MBP-iCP9-induced oligodendrocyte apoptosis compromised the rate and extent of adult remyelination. Remyelination failure correlated with a truncated proliferative response of oligodendrocyte progenitor cells, suggesting that depleting the oligodendrocyte pool during critical developmental periods compromises the regenerative response to subsequent demyelinating lesions.
  
  
  CONCLUSIONS
  This manuscript demonstrates that early insults leading to oligodendrocyte apoptosis result in the impairment of recovery from demyelinating diseases in the adult. These studies begin to provide an initial understanding of the potential failure of recovery in insults, such as periventricular leukomalacia and multiple sclerosis.
authors.affiliation: Department of Neurosciences, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106, Department of Clinical Neurosciences, University of Calgary Hotchkiss Brain Institute, Calgary, Alberta AB T2N 4N1, Canada, and.
authors.forename: Andrew V
authors.identifier: http://orcid.org/0000-0002-2529-5621
authors.initials: AV
authors.lastname: Caprariello
authors.affiliation: Department of Neurosciences, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106.
authors.forename: Courtney E
authors.initials: CE
authors.lastname: Batt
authors.affiliation: Department of Neurosciences, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106.
authors.forename: Ingrid
authors.initials: I
authors.lastname: Zippe
authors.affiliation: Department of Neurosciences, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106.
authors.forename: Rita R
authors.initials: RR
authors.lastname: Romito-DiGiacomo
authors.affiliation: Department of Anatomy and Regenerative Biology, George Washington University, Washington, DC 20037.
authors.forename: Molly
authors.initials: M
authors.lastname: Karl
authors.affiliation: Department of Neurosciences, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106, Department of Anatomy and Regenerative Biology, George Washington University, Washington, DC 20037 Rhm3@email.gwu.edu.
authors.forename: Robert H
authors.initials: RH
authors.lastname: Miller
mesh_terms: D000367:Age Factors; D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000235:genetics*; D053453:Caspase 9 / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D003711:Demyelinating Diseases / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D019281:Dimerization; D004195:Disease Models, Animal; D005260:Female; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D008244:Lysophosphatidylcholines / Q000494:pharmacology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D004676:Myelin Basic Protein / Q000235:genetics; D009836:Oligodendroglia / Q000473:pathology* / Q000648:ultrastructure; D010982:Platelet-Derived Growth Factor / Q000378:metabolism; D013116:Spinal Cord / Q000254:growth & development* / Q000473:pathology*; D014404:Tubulin / Q000378:metabolism
chemical_list: D005904:Glial Fibrillary Acidic Protein; D008244:Lysophosphatidylcholines; D004676:Myelin Basic Protein; D010982:Platelet-Derived Growth Factor; D014404:Tubulin; C462941:beta3 tubulin, mouse; C506434:Casp9 protein, mouse; D053453:Caspase 9
keywords: development; lysolecithin; myelination; oligodendrocyte