Novel roles for metallothionein-I + II (MT-I + II) in defense responses, neurogenesis, and tissue restoration after traumatic brain injury: insights from global gene expression profiling in wild-type and MT-I + II knockout mice.
Traumatic injury to the brain is one of the leading causes of injury-related death or disability, especially among young people. Inflammatory processes and oxidative stress likely underlie much of the damage elicited by injury, but the full repertoire of responses involved is not well known. A genomic approach, such as the use of microarrays, provides much insight in this regard, especially if combined with the use of gene-targeted animals. We report here the results of one of these studies comparing wild-type and metallothionein-I + II knockout mice subjected to a cryolesion of the somatosensorial cortex and killed at 0, 1, 4, 8, and 16 days postlesion (dpl) using Affymetrix genechips/oligonucleotide arrays interrogating approximately 10,000 different murine genes (MG_U74Av2). Hierarchical clustering analysis of these genes readily shows an orderly pattern of gene responses at specific times consistent with the processes involved in the initial tissue injury and later regeneration of the parenchyma, as well as a prominent effect of MT-I + II deficiency. The results thoroughly confirmed the importance of the antioxidant proteins MT-I + II in the response of the brain to injury and opened new avenues that were confirmed by immunohistochemistry. Data in KO, MT-I-overexpressing, and MT-II-injected mice strongly suggest a role of these proteins in postlesional activation of neural stem cells.
Penkowa
Milena
M
Section of Neuroprotection, Centre of Inflammation and Metabolism, The Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark.
Cáceres
Mario
M
Borup
Rehannah
R
Nielsen
Finn Cilius
FC
Poulsen
Christian Bjørn
CB
Quintana
Albert
A
Molinero
Amalia
A
Carrasco
Javier
J
Florit
Sergi
S
Giralt
Mercedes
M
Hidalgo
Juan
J
D000704:Analysis of Variance; D000818:Animals; D051399:Aquaporin 2 / Q000378:metabolism; D001930:Brain Injuries / Q000188:drug therapy / Q000378:metabolism* / Q000503:physiopathology*; D002374:Catalase / Q000378:metabolism; D016000:Cluster Analysis; D020869:Gene Expression Profiling / Q000379:methods; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology*; D007150:Immunohistochemistry / Q000379:methods; D008668:Metallothionein / Q000172:deficiency / Q000502:physiology* / Q000627:therapeutic use; D051379:Mice; D018345:Mice, Knockout; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D013234:Stem Cells / Q000187:drug effects / Q000502:physiology*; D013997:Time Factors
D051399:Aquaporin 2; D008668:Metallothionein; D002374:Catalase; C498977:Mok protein, mouse; D020928:Mitogen-Activated Protein Kinases