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ISDN2012_0238: Reelin upregulation and impaired Purkinje cell functional organization following maternal exposure of deltamethrin in rat
Author(s) -
Kumar K.,
Patro N.,
Patro I.K.
Publication year - 2012
Publication title -
international journal of developmental neuroscience
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.761
H-Index - 88
eISSN - 1873-474X
pISSN - 0736-5748
DOI - 10.1016/j.ijdevneu.2012.10.047
Subject(s) - citation , neuroscience , reelin , library science , psychology , cognitive science , computer science , medicine , receptor
hereditary fatal childhood leukodystrophy, caused by mutation in aspartoacylase (ASPA) gene. In normal brain ASPA gene expression occurs in oligodendrocytes (OLs) and its first expression coincides with appearance of OL progenitors at embryonic stage E12.5 in the forebrain. A sign of hypomyelination, which correlates with pathophysiology of CD in young children, is detected in ASPA KO mouse brain during peak of myelination. In these mutant brains a continued proliferation of immature OLs, presence of highly acetylated histones H3 associated with epigenetic regulation of cell proliferation is observed. The process of myelin synthesis and myelination normally proceeds with repression of proliferation and initiation of differentiation/maturation of OLs. In order to understand developmental changes in gene expression and involvement of biological mechanisms in devastating demyelinating disease, we performed gene array analysis, microRNA and Metabolomics studies of normal and ASPA KO mouse cortical white matter (WM) tissue at P20, at the peak of myelination. Many studies have revealed the involvement of a set of required genes that play critical role in the process of normal OL maturation and myelination. However, alteration in regulatory mechanisms involving WM disorders is not understood at this time. We have identified a set of 331 negative and one of144 positive, differentially expressed genes between KO vs. wt WM. The gene ontology report shows down-regulation of a number of key genes belonging to the myelin family, as well as embryonic and postnatal developmental genes, which we are currently validating. Most significant observation includes increased oxidative stress during early developmental stages. Among several relevant molecular pathways, a cluster of histone genes are identified that are involved in nucleosome assembly or disassembly, modification of histones with indicated epigenetic role in the leukodystrophy.