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Anthea Letsou

Professor of Human Genetics

Anthea Letsou

B.A. Harvard University

Ph.D. Yale University

Research

References

aletsou@genetics.utah.edu

Anthea Letsou's Lab Page

Anthea Letsou's PubMed Literature Search

Molecular Biology Program

Embryonic Development, Neurometabolic Disease, Neurodegenerative Disease, Drosophila

Research

In The high degree of conservation of fundamental biological processes in humans and flies, coupled with the broad repertoire of fly genetic approaches makes Drosophila a uniquely powerful system for modeling human development and disease. In my lab we consider both embryonic and adult stages of development- using the fly to gain insights into human developmental abnormalities and disease, including neural tube defects such as spina bifida and neurodegenerative disorders such as Adrenoleukodystrophy.

1. Neural Tube Defects

We have employed genetic methods to identify, clone, and characterize genes required for dorsal closure, the morphogenetic process by which the embryonic lateral epidermal sheets spread dorsally to encase the developing embryo. Virtually all of the molecules essential for the changes in epithelial cell shape and position that drive dorsal closure are conserved and required for analogous vertebrate closure processes, including wound healing, and eyelid and neural tube fusion. Our ability to dissect and characterize dorsal closure in the experimentally tractable fruit fly enhances our understanding of the analogous processes in higher animals.

Our work has contributed significantly to our understanding of the JNK (Jun N-terminal kinase) and Dpp (Decapentaplegic) signaling cascades that function sequentially to direct dorsal closure. More recently, we have focused our studies on Raw (a novel protein) and Mummy (a UDP-N-acetylglucosamine pyrophosphorylase) and have identified a novel mechanism of JNK/AP-1 signaling antagonism. These studies are particularly significant as they allow us to find answers to unresolved questions of how the diverse JNK/AP-1 and Dpp pathway outputs translate into morphogenetic events (such as epithelial sheet movements) that are critical to the generation of tissues and organisms.

2. Neurodegeneration

Adrenoleukodystrophy (ALD) is a rare and oftentimes fatal progressive neurodegenerative disease. The most common form of the disease is X-linked (X-ALD); it occurs equally in all ethnic groups with an estimated incidence of 1:17,000. X-ALD is a clinically heterogeneous disorder, exhibiting incomplete penetrance and variable expressivity. Indeed, accumulation of saturated VLCFAs is a known biochemical hallmark of X-ALD (Igarashi et al., 1976). The gene responsible for X-ALD has been cloned and shown to encode a peroxisomal half ATP-binding-cassette transporter (ABCD1). The 745 amino acid ABCD1 protein localizes to the peroxisomal membrane, where like other members of the ABC (ATP-binding cassette) transporter family, it functions to transport very long chain fatty acids (VLCFAs, 22 or more carbons) via their acyl-CoA esters into peroxisomes where they are degraded by β-oxidation. Indeed, accumulation of saturated VLCFAs is a known biochemical hallmark of X-ALD. All X-ALD patients, including asymptomatic carriers show elevated levels of VLCFAs in the plasma, brain, and adrenal gland.

Currently there are no good treatments for ALD, and the precise mechanisms through which VLCFA concentrations cause ALD are still unknown. Moreover, what previous controversial mouse and fly models of disease ignore is the potential redundancy within the transporter and synthetase gene families that control VLCFA metabolism. Thus, to better understand the evolution and overlapping biochemical functions of the many VLCFA synthetases in flies and humans, we turned to double mutant studies in Drosophila. We have shown that the consequences of knocking out duplicated VLCFA synthetase genes (bubblegum and double bubble) are profound, and have thus generated the first powerful animal model for ALD. From the perspective of disease etiology and treatment, our data indicate that ALD is a disease of lipid and membrane-rich cells, and that accumulation of fatty acids does lead to cell death in affected areas of the brain. Currently, we are exploiting our model to (1) identify the mechanism of cell death in support cells of the nervous system, (2) identify other factors (genes) affecting VLCFA metabolism in the brains, and (3) screen for drugs effective in the treatment of this devastating disease.

References

  1. Byington CL, Rothwell E, Matheson T, Childs R, Wachs E, Rocha R, Murtaugh M, Turok D, Letsou A, Shakib J, Hess R, Dere MW (in press). Developing Sustainable Research Careers for KL2 Scholars: The Importance of an Inclusive Environment and Mentorship. J. Clin. Trans. Sci
  2. Sivachenko A, Gordon HB, Kimball SS, Gavin EJ, Bonkowsky JL, Letsou A (2016) Neurodegeneration in a Drosophila model of adrenoleukodystrophy: the roles of the Bubblegum and Double bubble acyl-CoA synthetases. Dis Model Mech 9:377-87
  3. Moulton MJ, Letsou A (2016) Modeling congenital disease and inborn errors of development in Drosophila melanogaster. Dis Model Mech 9:253-69
  4. Gordon HB, Letsou A, Bonkowsky JL (2014) The leukodystrophies. Semin Neurol 34:312-20
  5. Humphreys GB, Jud MC, Monroe KM, Kimball SS, Higley M, Shipley D, Vrablik MC, Bates KL, Letsou A (2013) Mummy, A UDP-N-acetylglucosamine pyrophosphorylase, modulates DPP signaling in the embryonic epidermis of Drosophila. Dev Biol 381:434-45
  6. Baranov PV, Wills NM, Barriscale KA, Firth AE, Jud MC, Letsou A, Manning G, Atkins JF (2011) Programmed ribosomal frameshifting in the expression of the regulator of intestinal stem cell proliferation, adenomatous polyposis coli (APC). RNA Biology 8:637-47
  7. Bates K, Higley M, Letsou A (2008) raw mediates antagonism of AP-1 activity in Drosophila. Genetics 178:1989-2002
  8. VanHook A, Letsou A (2008) Head Involution in Drosophila: Genetic and Morphogenetic Connections to Dorsal Closure. Dev. Dyn. 237:28-38
  9. Scuderi A, Simin K, Kazuko SG, Metherall JE, Letsou A (2006) scylla and charybde, homologues of the human apoptotic gene RTP801, are required for head involution in Drosophila. Dev. Biol. 291:110-22
  10. Scuderi A, Letsou A (2005) The Amnioserosa is required for dorsal closure in Drosophila. Dev. Dyn. 232:791-800
  11. Letsou A, Bohmann D (2005) Small Flies - Big Discoveries: Nearly a Century of Drosophila Genetics and Development. Dev. Dyn. 232:526-528
  12. VanHook A, Letsou A (2004) Bully for Bugs. Dev. Dyn. 229:411-412
  13. Simin K, Scuderi A, Reamey J, Weiss R, Metherall JE, Letsou A (2002) Profiling patterned transcripts in Drosophila embryos. Genome Res. 12:1040-7
  14. Li X, Scuderi A, Letsou A, Virshup DM (2002) B56-Associated Protein Phosphatase 2A Is Required for Survival and Protects from Apoptosis in Drosophila. Mol. Cell Biol. 22:3674-84
  15. Byars CL, Bates KL, Letsou A (1999) The dorsal-open group gene raw is required for restricted DJNK signaling during closure. Development 126:4913-23
  16. Simin K, Bates E, Horner M, Letsou A (1998) Genetic analysis of Punt, a type II Dpp receptor that functions throughout the Drosophila melanogaster lifecycle.  Genetics 148:801-813

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Last Updated: 8/21/17