Pluripotent stem cells with the ability to form both neurons and glial cells are present from the earliest stages of embryonic development through senescence. Despite considerable interest, little is known regarding the signaling molecules, growth factors, or the extracellular matrix (ECM) molecules that create the local microenvironment of tissue (neural) stem cells. Recent evidence suggests that in the growth factor and ECM depleted adult CNS, the major stem cell region in the subventricular zone (SVZ) is maintained by noggin-BMP interactions. Like other stem cell """"""""niches"""""""", noggin (produced by the ependyma) promotes neuronal differentiation, while BMP2, 4 produced by neural stem cells antagonize neuronal differentiation activity to maintain the stem cell phenotype. The goal of the current investigation is to determine the role of noggin in producing a neurogenic environment in vivo, in maintaining the SVZ stem cell niche, and in promoting repair following injury. Our initial goal is to produce a line of transgenic mice in which noggin can be expressed in neural stem cells via the CNS restricted nestin second intronic enhancer. Experiments to determine the prenatal and postnatal effects of trensgenic noggin expression will further characterize these animals, the neural stem cell, and the role of noggin in neuronal differentiation. We will determine the potential of noggin to promote CNS repair in two injury models. In the first, the noggin producing ependyma will be removed producing a localized gliosis, then noggin expression induced in SVZ stem cells at various timepoints following injury. In the second, more traditional stroke model, the middle cerebral artery will be occluded and noggin gene expression induced. Because stem cells themselves provide important models to study lineage choice during differentiation, in the longer term, neural stem cells will be derived from trensgenic animals and their differentiation potential determined in vitro and when transplanted to the normal and injured CNS. These studies will provide valuable new data regarding the role of this potent neurogenic molecule during CNS development, in maintaining the regional neural stem cell niche, and will set the stage to directly examine noggin/BMP interactions in additional models of CNS injury and repair. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS048187-04
Application #
7243360
Study Section
Special Emphasis Panel (ZRG1-CDIN (01))
Program Officer
Owens, David F
Project Start
2004-06-07
Project End
2009-05-31
Budget Start
2007-06-01
Budget End
2009-05-31
Support Year
4
Fiscal Year
2007
Total Cost
$294,056
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Tsan, Yao-Chang; Morell, Maria H; O'Shea, K Sue (2016) miR-410 controls adult SVZ neurogenesis by targeting neurogenic genes. Stem Cell Res 17:238-247
Morell, M; Tsan, Yao-chang; O'Shea, K Sue (2015) Inducible expression of noggin selectively expands neural progenitors in the adult SVZ. Stem Cell Res 14:79-94
Purcell, Erin K; Yang, Amy; Liu, Liqian et al. (2013) BDNF profoundly and specifically increases KCNQ4 expression in neurons derived from embryonic stem cells. Stem Cell Res 10:29-35
Watanabe, Reiko; Morell, Maria H; Miller, Josef M et al. (2012) Nestin-expressing cells in the developing, mature and noise-exposed cochlear epithelium. Mol Cell Neurosci 49:104-9
Garcia-Perez, Jose L; Morell, Maria; Scheys, Joshua O et al. (2010) Epigenetic silencing of engineered L1 retrotransposition events in human embryonic carcinoma cells. Nature 466:769-73
Torisawa, Yu-suke; Mosadegh, Bobak; Luker, Gary D et al. (2009) Microfluidic hydrodynamic cellular patterning for systematic formation of co-culture spheroids. Integr Biol (Camb) 1:649-54
Coufal, Nicole G; Garcia-Perez, José L; Peng, Grace E et al. (2009) L1 retrotransposition in human neural progenitor cells. Nature 460:1127-31
Davidson, Ann E; Gratsch, Theresa E; Morell, Maria H et al. (2009) Use of the Sleeping Beauty transposon system for stable gene expression in mouse embryonic stem cells. Cold Spring Harb Protoc 2009:pdb.prot5270
Reyes, Jeannie H; O'Shea, K Sue; Wys, Noel L et al. (2008) Glutamatergic neuronal differentiation of mouse embryonic stem cells after transient expression of neurogenin 1 and treatment with BDNF and GDNF: in vitro and in vivo studies. J Neurosci 28:12622-31
Altschuler, Richard A; O'Shea, K Sue; Miller, Josef M (2008) Stem cell transplantation for auditory nerve replacement. Hear Res 242:110-6

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