Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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Transcription profiling of spinal cords from nmd mice tranplanted with ALDHhiSSClo neural stem cells to study molecular mechanism of delayed SMARD1 disease progression induced by the transplantation.

ABSTRACT: SMARD1 is an infantile autosomal recessive motor neuron (MN) disease, caused by mutations in the Immunoglobulin mu binding protein 2 (IGHMBP2). We investigated the potential of a spinal cord neural stem cell population isolated on the basis of aldehyde dehydrogenase activity (ALDH) to modify disease progression of nmd mice, an animal model of SMARD1. ALDHhiSSClo stem cells are self-renewing and multipotent and when intratechally transplanted in nmd mice generate motor neurons properly localized in the spinal cord ventral horns. Transplanted nmd animals presented delayed disease progression, sparing of motor neurons and ventral root axons and increased life-span. To further investigate the molecular events responsible for these differences, microarray and Real time RT-PCR analysis of wild-type, mutated and transplanted nmd spinal cord were undertaken. We demonstrated a down-regulation of genes involved in excitatory amino acid toxicity and oxidative stress handling, as well as an up-regulation of genes related to the chromatin organization in nmd compared to wild-type mice, suggesting that they may play a role in SMARD1 pathogenesis. Spinal cord of nmd transplanted mice expressed high transcript levels for genes related to neurogenesis such as Doublecortin (DCX), LIS1 and drebrin. The presence of DCX-expressing cells in adult nmd spinal cord suggests that both exogenous and endogenous neurogenesis may contribute to the observed nmd phenotype amelioration. Experiment Overall Design: We intratechally transplanted a spinal cord neural stem cell population isolated on the basis of aldehyde dehydrogenase activity (ALDH) in nmd mice, an animal model of SMARD1. Experiment Overall Design: We analyzed the lumbar spinal cord tract of transplanted nmd mice (n=3), untransplanted nmd mice (n=3) and wild-type mice (n=3) (all mice are of male gender). The latter groups underwent surgical procedure with vehicle. The surgical procedure and cell transplantation were done at P1 and the animals were sacrificed at 6 weeks of age.

ORGANISM(S): Mus musculus

DISEASE(S): SMARD1

SUBMITTER: Stefania Corti

PROVIDER: E-GEOD-3075 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

Transplanted ALDHhiSSClo neural stem cells generate motor neurons and delay disease progression of nmd mice, an animal model of SMARD1.

Corti Stefania S Locatelli Federica F Papadimitriou Dimitra D Donadoni Chiara C Del Bo Roberto R Crimi Marco M Bordoni Andreina A Fortunato Francesco F Strazzer Sandra S Menozzi Giorgia G Salani Sabrina S Bresolin Nereo N Comi Giacomo P GP

Human molecular genetics 20051208 2

Spinal muscular atrophy with respiratory distress type 1 (SMARD1) is an infantile autosomal-recessive motor neuron disease caused by mutations in the immunoglobulin micro-binding protein 2. We investigated the potential of a spinal cord neural stem cell population isolated on the basis of aldehyde dehydrogenase (ALDH) activity to modify disease progression of nmd mice, an animal model of SMARD1. ALDH(hi)SSC(lo) stem cells are self-renewing and multipotent and when intrathecally transplanted in n ...[more]

PMID: 16339214

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Project description:Egr3 is a zinc-finger transcription factor involved in growth and development. Egr3-deficient mice have severe sensory ataxia due to failed development of muscle spindle stretch receptors. Sensory and motor neurons that normally innervate spindles are absent in Egr3-deficient mice, presumably as a secondary consequence to the loss of trophic signals produced by spindles during development that are required for innervation and neuron survival. The molecular mechanisms involving motor neuron fate specification, target derived growth factor dependencies, and specification of target innervation have been difficult to study since select markers for functionally specific motor neurons are very poorly characterized. A more thorough understanding of the molecular mediators of motor neuron biology will be important to evaluate the efficacy of new strategies devised to thwart neuron death that occurs in a variety of human motor neuronopathies and neuropathies. To identify genes specifically expressed by spinal cord fusimotor neurons: Many motor neuron specific genes have been described over the years. However, none have been described that distinguish fusimotor neurons from skeletomotor neurons despite the fact that they have distinct muscle targets (muscle spindle stretch receptors) and comprise 25-30% of the spinal motor neuron populations. Since these motor neurons have remarkably different target innervation and function, we hypothesize that they express genes that establish their specific phenotypes during development. We hypothesize that fusimotor neurons can be distinguished in the spinal cord by characterizing fusimotor neuron specific gene expression. Once fusimotor neuron specific genes are identified, they will be used as markers to identify fusimotor neurons in complex neuroglial cell populations in vivo and in vitro. We hypothesize that by characterizing fusimotor neuron specific genes, unique marker molecules will be identified for in vivo and in vitro study of this functionally distinct and important motor neuron subtype. Moreover, we hypothesize that many of the genes that are specifically expressed by fusimotor neurons will be involved in mechanisms related to their fate specification, target innervation and growth factor dependent biology. We will use the Affymetrix microarray platform to identify genes that are specifically expressed by fusimotor neurons in mouse spinal cord. The differential expression analysis will be performed on microdissected segments of spinal cord (L3-L5) from wild type and Egr3-deficient mice. Postnatal Egr3-deficient mice lack muscle spindles and fusimotor neurons in their spinal cords. By comparing gene expression from microdissected segments of spinal cord (L3-L5) between wild type and Egr3-deficient mice, we hypothesize that fusimotor neuron selective genes can be identified. We will microdissect L3-L5 segments of spinal cord using precise anatomical landmarks to ensure that comparable spinal cord regions are anlayzed from each animal. For each microarray experiment, total RNA will be extracted from L3-L5 cords (approximately 2 mm length of spinal cord). The integrity of each RNA sample will be verified by gel electrophoresis. The intact RNA samples from mice of similar genotype will be pooled from three (3) 27-day old animals. The intact cord dissection is easier in young animals (eg: 27-day old) and the phenotype is known to exist at this developmental stage. The RNA from each animal of a similar genotype will be pooled into a single sample to minimize false positive gene calls that may represent genes related to the specific state of vigilance of a particular animal at the time of sacrifice (eg: activity dependent genes). Thus, each of the two RNA samples to be analyzed for a particular microarray experiment will represent RNA from three (3) spinal cords of each genotype. RNA amplification for probe synthesis should not be necessary since we will provide 7 ug of intact pooled total RNA for each sample. For statistical analysis, the experiment will be performed twice. Since the RNA samples are precious, they will be provided to the Array Consortium in two shipments with each of the experiments performed independently.

Dataset Information

Transcription profiling of spinal cords from nmd mice tranplanted with ALDHhiSSClo neural stem cells to study molecular mechanism of delayed SMARD1 disease progression induced by the transplantation.

Publications

Transplanted ALDHhiSSClo neural stem cells generate motor neurons and delay disease progression of nmd mice, an animal model of SMARD1.

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