The Beattie Lab investigates the biological basis of motoneuron diseases with a focus on spinal muscular atrophy (SMA) and amyotrophic lateral sclerosis (ALS).
Lab members are also interested in the genetic and molecular mechanisms that promote motoneuron development, such as the cues that guide motor axons to their target muscles and the formation of the connections between motoneurons and muscle. The lab has also recently started a project modeling glioblastoma to characterize the mechanism of tumor cell migration in the brain and to generate an animal model for efficient drug screening. Zebrafish is the vertebrate model organism used in this lab, due to their well-characterized nervous system and relatively simple neuromuscular organization. Moreover, by modeling diseases in zebrafish, researchers in the Beattie Lab are able to develop new approaches, such as genetic and drug screens, to identify targets that may alleviate the disease process.
Min An, MD, PhD
Hao Le, MD
Tessa Carrel, PhD
Adjunct Professor of Anatomy, Columbus College of Art and Design
Anil Challa, PhD
Research Instructor, University of Alabama, Genetics Research Division
Michelle Gray, PhD
Assistant Professor, University of Alabama Dept of Neurology
Alison Lyon, PhD
Navicore Group LLC, Medical writer
Michelle McWhorter, PhD
Associate Professor, Wittenberg University Dept of Biology
Tennore Ramesh, PhD
Lecturer, Academic Neurology, University of Sheffield
Louise Rodino-Klapac, PhD
Assistant Professor, Center for Gene Therapy, Nationwide Children's Hospital
Biological basis of the motoneuron disease Spinal Muscular Atrophy (SMA) and ALS
Now, they’re focused on understanding how SMN functions in motoneuron development and how this affects motor circuit formation. In particular they are focusing on the interaction between SMN and RNA binding proteins (eg HuD, Zbp1, Zbp2) that facilitate motoneuron development by stabilizing and/or localizing RNAs in growing axons and dendrites.
Amyotrophic lateral sclerosis is an adult onset, fatal motoneuron degenerative disease that has no cure and limited therapies. The lab has generated a genetic model of ALS that reveals hallmarks of the disease including motoneuron loss and letality. Their goal is to understand the early changes in the spinal cord of these animals as a way to better understanding the mechanism of motoneuron dysfunction in ALS.
Using zebrafish to study brain cancer
Glioblastoma (GBM) is a deadly brain cancer with few effective drug treatments available. To facilitate analysis of glioblastoma tumor cell behavior in real time and to develop new approaches for GBM drug screens, the Beattie Lab has generated and standardized a xenotransplant model of GBM in zebrafish. Using this standardized approach, they have transplanted two patient-derived GBM cell lines, serum grown adherent cells (X12) and neurospheres (GBM9) into the midbrain region of embryonic zebrafish. Analysis of larvae over time showed progressive brain tumor growth and premature death with both cell lines, however, fewer GBM9 cells were needed to cause tumor growth and lethality. Approximately half of the cells in both xenotransplants were dividing whereas control mouse neural stem cells failed to engraft and were cleared from the brain. GBM9 cells differentiated over time in vivo, whereas X12 differentiated very early suggesting that these tumors were less dynamic in vivo. Both cell types generated tumors that contained Sox2-positive cells indicative of neural stem cells. To determine whether GBM9 tumors were responsive to currently used therapeutics, they treated transplanted larvae with either temozolomide or bortezomib and found a reduction in tumor volume in-vivo and an increase in survival supporting the use of this standardized model for drug screening. The lab is now focused on understanding what types of tumor cells survive drug treatment and whether these cells can generate new tumors. Moreover, in collaboration with colleagues on campus, they are testing novel drug compounds for efficacy against GBM using this new model.
Carrel TL, McWhorter ML, Workman E, Zhang H, Wolstencroft EC, Lorson C, Bassell G, Burghes AHM, and Beattie CE.(2006) SMN function in motor axons is independent of functions required for snRNP biogenesis. Journal of Neuroscience 26:11014–11022. Highlighted in This Week in the Journal.
McWhorter ML, Boon K, Horan ES, Burghes AHM, and Beattie CE. (2008) The SMN complex protein Gemin2 is not involved in zebrafish motor axon outgrowth. Developmental Neurobiology 68:182–94.
Oprea GE, Kröber S, McWhorter ML, Rossoll W, Müller S, Krawczak M, Bassell GJ, Beattie CE, and Wirth B. (2008) Plastin 3 is a Protective Modifier of Autosomal Recessive Spinal Muscular Atrophy. Science 320:524–527.
Boon KL, Xiao S, McWhorter ML, Donn T, Wolf-Saxon E, Bohnsack MT, Moens CB, Beattie CE. (2009) Zebrafish survival motor neuron Mutants Exhibit Presynaptic Neuromuscular Junction Defects. Human Molecular Genetics 18:3615–3625.
Burghes AH and Beattie CE. (2009) Spinal muscular atrophy: why do low levels of survival motor neuron protein make motor neurons sick? Nature Reviews Neuroscience 10: 597–609.
Ramesh T, Lyon AN, Pineda RH, Wang C, Janssen PML, Canan BD, Burghes AHM, and Beattie CE. (2010) A genetic model of amyotrophic lateral sclerosis in zebrafish displays phenotypic hallmarks of motoneuron disease. Disease Models and Mechanisms 3:652–662.
Hao le T, Burghes AHM, and Beattie CE. (2011) Generation and Characterization of a genetic zebrafish model of SMA carrying the human SMN2 gene. Molecular Neurodegeneration 6:24.
Akten B, Kye MJ, Hao le T, Wertz MH, Singh S, Nie D, Huang J, Merianda TT, Twiss JL, Beattie CE, Steen JA, and Sahin M. (2011) Interaction of survival of motor neuron (SMN) and HuD proteins with mRNA cpg15 rescues motor neuron axonal defects. Proc Natl Acad Sci U.S.A. 108:10337–10342.
Hao le T, Wolman M, Granato M, Beattie CE. (2012) Survival motor neuron affects plastin 3 levels leading to motor defects. Journal of Neuroscience 32:5074–5084.
Lotti F, Imlach WL, Saieva L, Beck ES, Hao LT, Li DK, Jiao W, Mentis GZ, Beattie CE, McCabe BD, and Pellizzoni L. (2012) A SMN-dependent U12 splicing event essential for motor circuit function. Cell 151:440–454.
McGown A, McDearmid JR, Panagiotaki N, Tong H, Al Mashhadi S, Redhead N, Lyon AN, Beattie CE, Shaw PJ, and Ramesh TM. (2013) Early interneuron dysfunction in ALS: Insights from a mutant sod1 zebrafish model. Annals of Neurolology 73:246–258.
Hao le T, Duy PQ, Jontes JD, Wolman M, Granato M, and Beattie CE. (2013) Temporal requirement for SMN in motoneuron development. Human Molecular Genetics 22:2612–2625.
Gassman A, Hao le T, Bhoite L, Bradford CL, Chien CB, Beattie CE, and Manfredi JP. (2013) Small molecule suppressors of Drosophila Kinesin deficiency rescue motor axon development in a zebrafish model of spinal muscular atrophy. PLoS One. 8(9):e74325.
Lyon AN, Pineda RH, Hao le T, Kudryashova E, Kudryashov DS, and Beattie CE. (2014) Calcium binding is essential for plastin 3 function in Smn-deficient motoneurons. Human Molecular Genetics 23(8):1990–2004.
Hao le T, Duy PQ, Jontes JD, and Beattie CE. (2015) Motoneuron development influences dorsal root ganglia survival and Schwann cell development in a vertebrate model of spinal muscular atrophy. Human Molecular Genetics 24:346–360.