| Associate Professor (also with Pediatrics and Neurology); Ph.D., Queensland (Australia), 1990. Role of the unfolded protein response in neurodegenerative diseases; molecular characterization of the regulation of axoglial junction assembly in CNS myelin; molecular characterization of the claudin family of integral membrane tight junction proteins during development in brain, testes, and inner ear using transgenic and homologous recombination in embryonic stem cells.
Research Interests
There are currently three funded projects in my laboratory:
1) Molecular Pathogenesis of Neurodegenerative Disease.
Over the past decade, we have identified an intracellular signaling pathway that is activated by mutant forms of the proteins encoded by the PLP1 gene, and leads to widespread death of oligodendrocytes, the cells that synthesize white matter in the brain. This signaling pathway is known as the unfolded protein response, and is under intense investigation by many laboratories throughout the world for its possible role in diseases such as Alzheimer disease, Parkinson disease and Huntington disease. We have demonstrated in our mouse model of pediatric neurodegenerative disease that the unfolded protein response plays a direct role in pathogenesis of the leukodystrophy, Pelizaeus-Merzbacher disease, and we are currently defining this signaling pathway in molecular detail using transgenic and gene-ablation approaches. To date we have identified a stress-induced transcription factor that modulates disease severity, and we are characterizing several other candidate protein, with the anticipation that we will identify proteins that we can use as pharmacological targets to ameliorate disease severity.
2) Function of Intercellular Junctions in Sensorineural Deafness.
Several years ago, we used gene-ablation to inactivate the Claudin 11 gene in mice. This gene encodes a tight junction protein that is widely expressed during development and adulthood and we have demonstrated that claudin 11 serves critical functions in nerve conduction in the CNS, spermatogenesis and auditory function. Currently, we are investigating the pathophysiology of sensorineural deafness in the knockout mice with a view to a deeper understanding of the function of the stria vascularis in normal cochlear function. In addition, the CLAUDIN 11 gene in humans maps to a region of chromosome 3 that is implicated in the disease, Cornelia De Lange syndrome and we are currently investigating CLAUDIN 11 as a candidate gene for this disease.
3) Function of the transcription factor, Nkx6-2, in regulating axon-glial interactions.
Several years ago, we used gene-ablation to inactivate the Nkx6-2 gene in mice. This gene encodes a homeodomain transcription factor and the mutant mice develop abnormalities in CNS myelin sheaths adjacent to nodes of Ranvier. This paranodal region of the myelin sheath is of prime importance to normal nerve conduction, particularly with regard to the adhesive junctions (called axoglial junctions) that form between myelin and the axon. We have found that the axoglial junctions are disrupted in Nkx6-2-null mice and that expression of 2 adhesive proteins by oligodendrocytes is dysregulated. These data suggest that Nkx6-2 may function to coordinately regulate axoglial junction formation, and we are currently attempting to identify other dysregulated genes using genomics and proteomics approaches. Ultimately, we anticipate that these studies will lead to the identification of the adhesive protein complex in the axoglial junction.
Selected Publications
1. Stecca B, Southwood CM, Gragerov A, Kelley KA, Friedrich VL, Gow A (2000) The evolution of lipophilin genes from invertebrates to tetrapods: DM-20 cannot replace proteolipid protein in CNS myelin. J. Neurosci. 20, 4002-4010.
2. Southwood CM and Gow A (2001) Insights into the mechanisms of oligodendrocyte apoptosis from hypomyelinated mice. Micros. Res. Tech. 52, 700-708.
3. Southwood CM, Gow A (2001) Functions of OSP/claudin 11-containing parallel tight junctions: implications from the knockout mouse. in Tight Junctions. (Anderson JM and Cereijido M, eds) 2nd Edn. CRC Press. pp. 723-745.
4. Gow A (2002) The COS-7 cell in vitro paradigm to study myelin proteolipid protein 1 gene mutations. in: Methods in Molecular Medicine, (Potter T, ed), Humana Press, Totowa and New Jersey, pp. 263-275.
5. Southwood CM, Garbern J, Jiang W, Gow A (2002) The unfolded protein response modulates disease severity in Pelizaeus-Merzbacher Disease. Neuron, 36, 585-596.
6. Shy M, Hobson G, Boespflug-Tanguy O, Garbern J, Sperle K, Jain M, Li W, Gow A, Rodriguez D, Bertini E, Mancias P, Krajewski K, Lewis RA, Kamholz J, members of the ENBDD (2003) Schwann cell expression of PLP1 but not its alternatively spliced isoform DM20 is necessary to prevent demyelinating peripheral neuropathy. Ann. Neurol., 53, 354-365.
7. Gow A, Sharma R (2003) The unfolded protein response in protein aggregating diseases. Neuromolec. Med., 4, 73-94.
8. Yang LV, Heng HH, Southwood CM, Gow A , Li L (2003) Alternate promoters and polyadenylation regulate tissue-specific expression of Hemogen isoforms during hematopoisis and spermatogenesis. Dev. Dyn. 228, 606-616.
9. Gow A (2004) The Claudin 11 gene. The Claudin 11 gene. In Myelin Biology and Disorders, (Lazzarini, RA ed.), Elsevier Science, pp. 565-578.
10. Gow A (2004) Protein misfolding as a disease determinant. In Myelin Biology and Disorders, (Lazzarini, RA ed.), Vol. 2, Elsevier Science, pp 1009-1036.
11. Gow A , Davies C, Southwood CM, Frolenkov G, Chrustowski M, Ng L, Yamauchi D, Marcus DC,
Kachar B (2004) Deafness in Claudin 11 -null mice reveals the critical contribution of basal cell
tight junctions to stria vascularis function. J Neurosci ., 24(32), 7051-7062.
12. Southwood CM, He C, Garbern J, Kamholz J, Arroyo E, Gow A (2004) CNS Myelin Paranodes
Require Nkx6-2 Homeoprotein Transcriptional Activity for Normal Structure. J Neurosci, 24,
11215-11225.
13. Xin M, Wu F-F, Ma Z, Gow A, Lu QR (2005) Myelinogenesis and axonal recognition by
oligodendrocytes in brain are uncoupled in Olig1-null mice. J Neurosci, 25, 1354-1365.
14. Hurst S, Garbern J, Trepanier A, Gow A (2006) Quantifying the carrier female phenotype in
Pelizaeus-Merzbacher disease. Genet Med, 8, 371-378.
15. Nunes FD, Lopez LN, Lin HW, Davies C, Azevedo RB, Gow A, Kachar B (2006) Distinct sub-
domain organization and molecular composition of a tight junction with cell-cell adhesion
properties. J Cell Sci, 119, 4819-4827.
16. Southwood CM, Peppi M, Dryden S, Tainsky MA, Gow A (2006) Microtubule deacetylases,
SirT2 and HDAC6, in the nervous system. Neurochem Res, 32, 187-195.
17. Southwood CM, Olson K, Wu C-Y, Gow A (2006) Novel alternatively-spliced ER retention
signal in the cytoplasmic loop of proteolipid protein 1. J Neurosci Res, 85, 471-478.
18. Sharma R, Gow A (2007) Minimal role for caspase-12 in the unfolded protein response in
oligodendrocytes in vivo. J Neurochem, 101, 889-897.
19. Sharma R, Jiang H, Zhong L, Tseng J, Gow A (2007) Minimal Role For Activating
Transcription Factor 3 In The Oligodendrocyte Unfolded Protein Response in vivo, J
Neurochem, 102, 1703-1712.
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