The lethal motor neuron diseases (MNDs) amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA) are defined by the loss of somatic motor neurons that innervate muscles in arms, legs, trunk and face, leading to muscle wasting. However, not all motor neurons are equally vulnerable; certain groups of motor neurons are spared, including those in the oculomotor nucleus, controlling eye movement and motor neurons in the Onuf's nucleus, controlling pelvic muscles. The reasons for the differential vulnerability to degeneration among motor neuron groups are unknown.
Research in the Hedlund lab is aimed at elucidating mechanisms of neuronal vulnerability and resistance with the goal of identifying new molecular targets for the treatment of motor neuron diseases.
Towards this goal, we utilize laser capture microdissection coupled with RNA sequencing to dissect molecular pathways in distinct motor neuron populations in animal models of MNDs. We also perform cross-disease analyses of degenerative and regenerative axonal responses at neuromuscular junctions - the specialized synapses between motor neurons and muscle.
Motor neuron cultures derived from embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) harboring disease-inducing mutations are coupled with microfluidics to model MNDs and study neuronal vulnerability and protection in vitro. Finally, we modulate candidate gene expression in vivo in transgenic MND mouse models to induce motor neuron protection and axonal regeneration.
Differential neuronal vulnerability identifies IGF-2 as a protective factor in ALS.
Sci Rep 2016 05;6():25960
Cross-disease comparison of amyotrophic lateral sclerosis and spinal muscular atrophy reveals conservation of selective vulnerability but differential neuromuscular junction pathology.
J. Comp. Neurol. 2016 May;524(7):1424-42
Motor neurons with differential vulnerability to degeneration show distinct protein signatures in health and ALS.
Neuroscience 2015 Apr;291():216-29
Presymptomatic activation of the PDGF-CC pathway accelerates onset of ALS neurodegeneration.
Acta Neuropathol. 2016 Mar;131(3):453-64
Selection Based on FOXA2 Expression Is Not Sufficient to Enrich for Dopamine Neurons From Human Pluripotent Stem Cells.
Stem Cells Transl Med 2014 Sep;3(9):1032-42
Cellular therapy to target neuroinflammation in amyotrophic lateral sclerosis.
Cell. Mol. Life Sci. 2014 Mar;71(6):999-1015
Specific and integrated roles of Lmx1a, Lmx1b and Phox2a in ventral midbrain development.
Development 2011 Aug;138(16):3399-408
Transcription factor-induced lineage selection of stem-cell-derived neural progenitor cells.
Cell Stem Cell 2011 Jun;8(6):663-75
Differential neuronal vulnerability identifies IGF-2 as a protective factor in ALS
Scientific reports 2016;6():25960-
Dopamine Receptor Antagonists Enhance Proliferation and Neurogenesis of Midbrain Lmx1a-expressing Progenitors
Scientific reports 2016;6():26448-
Laser capture microscopy coupled with Smart-seq2 for precise spatial transcriptomic profiling
Nature communications 2016;7():12139-
Presymptomatic activation of the PDGF-CC pathway accelerates onset of ALS neurodegeneration
Acta neuropathologica 2016;131(3):453-64
Single-cell analyses of X Chromosome inactivation dynamics and pluripotency during differentiation
Genome research 2016;26(10):1342-1354
Motor neurons with differential vulnerability to degeneration show distinct protein signatures in health and ALS
Cellular therapy to target neuroinflammation in amyotrophic lateral sclerosis
Cellular and molecular life sciences : CMLS 2014;71(6):999-1015
Directed midbrain and spinal cord neurogenesis from pluripotent stem cells to model development and disease in a dish
Frontiers in neuroscience 2014;8():109-
Selection Based on FOXA2 Expression Is Not Sufficient to Enrich for Dopamine Neurons From Human Pluripotent Stem Cells
Stem cells translational medicine 2014;3(9):1032-42
Cellular programming and reprogramming: sculpting cell fate for the production of dopamine neurons for cell therapy
Stem cells international 2012;2012():412040-
Specific and integrated roles of Lmx1a, Lmx1b and Phox2a in ventral midbrain development
The protective effects of beta-lactam antibiotics in motor neuron disorders
EXPERIMENTAL NEUROLOGY 2011;231(1):14-8
Transcription Factor-Induced Lineage Selection of Stem-Cell-Derived Neural Progenitor Cells
CELL STEM CELL 2011;8(6):663-75
Neuronal cell replacement in Parkinson's disease
JOURNAL OF INTERNAL MEDICINE 2009;266(4):358-71
ALS Model Glia Can Mediate Toxicity to Motor Neurons Derived from Human Embryonic Stem Cells
CELL STEM CELL 2008;3(6):575-6
Embryonic stem cell-derived Pitx3-enhanced green fluorescent protein midbrain dopamine neurons survive enrichment by fluorescence-activated cell sorting and function in an animal model of Parkinson's disease
STEM CELLS 2008;26(6):1526-36
Neurons derived from reprogrammed fibroblasts functionally integrate into the fetal brain and improve symptoms of rats with Parkinson's disease
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 2008;105(15):5856-61
Cell therapy and stem cells in animal models of motor neuron disorders
EUROPEAN JOURNAL OF NEUROSCIENCE 2007;26(7):1721-37
Selection of embryonic stem cell-derived enhanced green fluorescent protein-positive dopamine neurons using the tyrosine hydroxylase promoter is confounded by reporter gene expression in immature cell populations
STEM CELLS 2007;25(5):1126-35
A tyrosine hydroxylase-yellow fluorescent protein knock-in reporter system labeling dopaminergic neurons reveals potential regulatory role for the first intron of the rodent tyrosine hydroxylase gene
Genetic selection of sox1GFP-expressing neural precursors removes residual tumorigenic pluripotent stem cells and attenuates tumor formation after transplantation
JOURNAL OF NEUROCHEMISTRY 2006;97(5):1467-80
L1 CAM expression is increased surrounding the lesion site in rats with complete spinal cord transection as neonates
EXPERIMENTAL NEUROLOGY 2005;194(2):363-75
The homeodomain transcription factor Pitx3 facilitates differentiation of mouse embryonic stem cells into AHD2-expressing dopaminergic neurons
MOLECULAR AND CELLULAR NEUROSCIENCE 2005;28(2):241-52
Identification of a Hoxd10-regulated transcriptional network and combinatorial interactions with Hoxa10 during spinal cord development
JOURNAL OF NEUROSCIENCE RESEARCH 2004;75(3):307-19
Region-specific cell grafting into cervical and lumbar spinal cord in rat: a qualitative and quantitative stereological study
EXPERIMENTAL NEUROLOGY 2004;190(1):122-32
Differential Pax6 promoter activity and transcript expression during forebrain development
MECHANISMS OF DEVELOPMENT 2002;114(1-2):171-5
Cytochrome P450 in the brain; A review
CURRENT DRUG METABOLISM 2001;2(3):245-63
Neurosteroid hydroxylase CYP7B - Vivid reporter activity in dentate gyrus of gene-targeted mice and abolition of a widespread pathway of steroid and oxysterol hydroxylation
JOURNAL OF BIOLOGICAL CHEMISTRY 2001;276(26):23937-44
Cytochrome P450 in the brain: 2B or not 2B
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Extrahepatic cytochrome P450: role in in situ toxicity and cell-specific hormone sensitivity
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Cytochrome P450 in the breast and brain: Role in tissue-specific activation of xenobiotics
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Cytochrome P4502D4 in the brain: Specific neuronal regulation by clozapine and toluene
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