TY - JOUR
T1 - Molecular networks perturbed in a developmental animal model of brain injury
AU - Kisby, G. E.
AU - Standley, M.
AU - Lu, X.
AU - O'Malley, J.
AU - Lin, B.
AU - Muniz, J.
AU - Luo, N. L.
AU - Pattee, P.
AU - Back, S. A.
AU - Nagalla, S. R.
N1 - Funding Information:
Supported by N.I.H. Grant 5P42-ES10338-02 [NIEHS Toxicogenomics Consortium] and, in part, by NIH grant ES10338-02 and DOD grant DAMD17-98-1-8625.
PY - 2005
Y1 - 2005
N2 - 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.
AB - 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.
KW - Cerebellum
KW - Cerebral cortex
KW - DNA damage
KW - Methylazoxymethanol (MAM)
KW - Microarray
KW - Proteasome
UR - http://www.scopus.com/inward/record.url?scp=20244379134&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=20244379134&partnerID=8YFLogxK
U2 - 10.1016/j.nbd.2004.11.014
DO - 10.1016/j.nbd.2004.11.014
M3 - Article
C2 - 15837566
AN - SCOPUS:20244379134
SN - 0969-9961
VL - 19
SP - 108
EP - 118
JO - Neurobiology of Disease
JF - Neurobiology of Disease
IS - 1-2
ER -