| 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.
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, 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.
3. Southwood CM, Garbern J, Jiang W, Gow A (2002) The unfolded protein response modulates disease severity in Pelizaeus-Merzbacher Disease. Neuron, 36, 585-596.
4. 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.
5. Gow A, Sharma R (2003) The unfolded protein response in protein aggregating diseases. Neuromolec. Med., 4, 73-94.
6. Gow A (2004) The Claudin 11 gene. The Claudin 11 gene. In Myelin Biology and Disorders, (Lazzarini, RA ed.), Elsevier Science, pp. 565-578.
7. Gow A (2004) Protein misfolding as a disease determinant. In Myelin Biology and Disorders, (Lazzarini, RA ed.), Vol. 2, Elsevier Science, pp 1009-1036.
8. 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.
9. 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.
10. 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.
11. Hurst S, Garbern J, Trepanier A, Gow A (2006) Quantifying the carrier female phenotype in
Pelizaeus-Merzbacher disease. Genet Med, 8, 371-378.
12. 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.
13. 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.
14. 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.
15. Sharma R, Gow A (2007) Minimal role for caspase-12 in the unfolded protein response in
oligodendrocytes in vivo. J Neurochem, 101, 889-897.
16. 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.
17. Elkouby-Naor L, Abassi Z, Lagziel A, Gow A, Ben-Yosef T(2008) Double gene deletion reveals the lack of cooperation between claudin 11 and claudin 14 tight junction proteins, Cell Tissue Res. 333, 427-438.
18. Devaux J, Gow A (2008) Tight Junctions Potentiate The Insulative Properties Of Small CNS Myelinated Axons, J Cell Biol, 183(5):909-21.
19. Gow A, Wrabetz L. (2009) CHOP and the endoplasmic reticulum stress response in myelinating glia, Curr Opin Neurobiol, in press.
20. Mazaud-Guittot S, Meugnier E, Pesenti S, Wu X, Vidal H, Gow A, Le Magueresse-Battistoni B (2009) Claudin 11 Deficiency in Mice Results in Loss of the Sertoli Cell Epithelial Phenotype in the Testis, Biol Reprod., in press.
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