Molecular networks perturbed in a developmental animal model of brain injury

G. E. Kisby, M. Standley, X. Lu, J. O'Malley, B. Lin, J. Muniz, N. L. Luo, P. Pattee, Stephen Back, S. R. Nagalla

Research output: Contribution to journalArticle

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Abstract

Methylazoxymethanol (MAM) is widely used as a developmental neurotoxin and exposure to its glucoside (i.e., cycasin) is associated with the prototypical neurological disorder western Pacific ALS/PDC. However, the specific molecular targets that play a key role in MAM-induced brain injury remain unclear. To reveal potential molecular networks targeted by MAM in the developing nervous system, we examined characteristic phenotypic changes (DNA damage, cytoarchitecture) induced by MAM and their correlation with gene expression differences using microarray assays (27,648 genes). Three day-old postnatal C57BL/6 mice (PND3) received a single injection of MAM and the cerebellum and cerebral cortex of PND4, 8, 15, and 22 mice were analyzed. DNA damage was detected in both the cerebellum (N7-mGua, TUNEL labeling) and cerebral cortex (N7-mGua) of PND4 mice, but progressive disruption of the cytoarchitecture was restricted to the cerebellum. A majority (>75%) of the genes affected (cerebellum 636 genes, cortex 1080 genes) by MAM were developmentally regulated, with a predominant response early (PND4) in the cerebellum and delayed (PND8 and 15) in the cerebral cortex. The genes and pathways (e.g., proteasome) affected by MAM in the cerebellum are distinct from cortex. The genes perturbed in the cerebellum reflect critical cellular processes such as development (17%), cell cycle (7%), protein metabolism (12%), and transcriptional regulation (9%) that could contribute to the observed cytoarchitectural disruption of the cerebellum. This study demonstrates for the first time that specific genes and molecular networks are affected by MAM during CNS development. Further investigation of these targets will help to understand how disruption of these developmental programs could contribute to chronic brain injury or neurodegenerative disease.

Original languageEnglish (US)
Pages (from-to)108-118
Number of pages11
JournalNeurobiology of Disease
Volume19
Issue number1-2
DOIs
StatePublished - Jun 2005

Fingerprint

Brain Injuries
Cerebellum
Animal Models
Cerebral Cortex
Genes
DNA Damage
Cycasin
Chronic Brain Injury
Cell Cycle Proteins
methylazoxymethanol
Gene Regulatory Networks
In Situ Nick-End Labeling
Glucosides
Neurotoxins
Brain Diseases
Proteasome Endopeptidase Complex
Nervous System Diseases
Inbred C57BL Mouse
Neurodegenerative Diseases
Nervous System

Keywords

  • Cerebellum
  • Cerebral cortex
  • DNA damage
  • Methylazoxymethanol (MAM)
  • Microarray
  • Proteasome

ASJC Scopus subject areas

  • Neurology

Cite this

Kisby, G. E., Standley, M., Lu, X., O'Malley, J., Lin, B., Muniz, J., ... Nagalla, S. R. (2005). Molecular networks perturbed in a developmental animal model of brain injury. Neurobiology of Disease, 19(1-2), 108-118. https://doi.org/10.1016/j.nbd.2004.11.014

Molecular networks perturbed in a developmental animal model of brain injury. / Kisby, G. E.; Standley, M.; Lu, X.; O'Malley, J.; Lin, B.; Muniz, J.; Luo, N. L.; Pattee, P.; Back, Stephen; Nagalla, S. R.

In: Neurobiology of Disease, Vol. 19, No. 1-2, 06.2005, p. 108-118.

Research output: Contribution to journalArticle

Kisby, GE, Standley, M, Lu, X, O'Malley, J, Lin, B, Muniz, J, Luo, NL, Pattee, P, Back, S & Nagalla, SR 2005, 'Molecular networks perturbed in a developmental animal model of brain injury', Neurobiology of Disease, vol. 19, no. 1-2, pp. 108-118. https://doi.org/10.1016/j.nbd.2004.11.014
Kisby, G. E. ; Standley, M. ; Lu, X. ; O'Malley, J. ; Lin, B. ; Muniz, J. ; Luo, N. L. ; Pattee, P. ; Back, Stephen ; Nagalla, S. R. / Molecular networks perturbed in a developmental animal model of brain injury. In: Neurobiology of Disease. 2005 ; Vol. 19, No. 1-2. pp. 108-118.
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