Reelin and CXCL12 regulate distinct migratory behaviors during the development of the dopaminergic system

Bodea, Gabriela O.; Spille, Jan-Hendrik; Abe, Philipp; Andersson, Aycan Senturk; Acker‐Palmer, Amparo; Stumm, Ralf; Kubitscheck, Ulrich; Blaess, Sandra

doi:10.1242/dev.099937

Cited by 46 publications

(118 citation statements)

References 70 publications

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“…Interestingly, RhoJ and Arl4D were validated as genes differentially regulated between C57 and Cav-1 KO and are both implicated in actinmediated cell migration (47,48). Furthermore, Cxcr4 was also validated as a differentially regulated gene and is implicated in dopaminergic cell migration (49). GC effects on neural stem cell migration are well documented (25).…”

Section: Discussionmentioning

confidence: 99%

Caveolin-1 Regulates Genomic Action of the Glucocorticoid Receptor in Neural Stem Cells

Peffer

Chandran

Luthra

et al. 2014

Molecular and Cellular Biology

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While glucocorticoids (GCs) are used clinically to treat many conditions, their neonatal and prenatal usage is increasingly controversial due to reports of delayed adverse outcomes, especially their effects on brain development. Such alterations may reflect the impact of GCs on neural progenitor/stem cell (NPSC) function. We previously demonstrated that the lipid raft protein caveolin-1 (Cav-1) was required for rapid GC signaling in embryonic mouse NPSCs operating through plasma membranebound glucocorticoid receptors (GRs). We show here that genomic GR signaling in NPSCs requires Cav-1. Loss of Cav-1 impacts the transcriptional response of many GR target genes (e.g., the serum-and glucocorticoid-regulated kinase 1 gene) that are likely to mediate the antiproliferative effects of GCs. Microarray analysis of wild-type C57 or Cav-1-deficient NPSCs identified approximately 100 genes that are differentially regulated by GC treatment. These changes in hormone responsiveness in Cav-1 knockout NPSCs are associated with the loss of GC-regulated phosphorylation of GR at serine 211 but not at serine 226. Chromatin recruitment of total GR to regulatory regions of target genes such as Fkbp-5, RhoJ, and Sgk-1, as well as p211-GR recruitment to Sgk-1, are compromised in Cav-1 knockout NPSCs. Cav-1 is therefore a multifunctional regulator of GR in NPSCs influencing both rapid and genomic action of the receptor to impact cell proliferation.

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Section: Discussionmentioning

confidence: 99%

Caveolin-1 Regulates Genomic Action of the Glucocorticoid Receptor in Neural Stem Cells

Peffer

Chandran

Luthra

et al. 2014

Molecular and Cellular Biology

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“…Cxcr4 (C-X-C motif chemokine receptor type 4) can be detected in the IZ and MZ (Fig. 3B) and is required for radial migration and fiber outgrowth of mDA neurons between E11.5 and E14.5 (Bodea et al, 2014;Yang et al, 2013b). Its ligand, Cxcl12 (C-X-C motif chemokine 12) is expressed in the meninges and is sufficient to promote the migration of mDA neurons (Yang et al, 2013b).…”

Section: Migration Of Postmitotic Mda Neuroblasts and Neuronsmentioning

confidence: 99%

How to make a midbrain dopaminergic neuron

2015

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Midbrain dopaminergic (mDA) neuron development has been an intense area of research during recent years. This is due in part to a growing interest in regenerative medicine and the hope that treatment for diseases affecting mDA neurons, such as Parkinson's disease (PD), might be facilitated by a better understanding of how these neurons are specified, differentiated and maintained in vivo. This knowledge might help to instruct efforts to generate mDA neurons in vitro, which holds promise not only for cell replacement therapy, but also for disease modeling and drug discovery. In this Primer, we will focus on recent developments in understanding the molecular mechanisms that regulate the development of mDA neurons in vivo, and how they have been used to generate human mDA neurons in vitro from pluripotent stem cells or from somatic cells via direct reprogramming. Current challenges and future avenues in the development of a regenerative medicine for PD will be identified and discussed.

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“…SDF-1␣ has been reported to function as an axonal guidance cue during development of many central nervous system (CNS) structures, including the substantia nigra, cerebellum, olfactory bulb, and corticospinal tracts, making the increased expression of SDF-1␣ following SCI a potentially efficacious strategy for encouraging axonal growth post-transplantation (Bodea et al, 2014;Lieberam, Agalliu, Nagasawa, Ericson, & Jessell, 2005;Toba, Tiong, Ma, & Wray, 2008;Zhu, Matsumoto, Mikami, Nagasawa, & Murakami, 2009). Additionally, the major receptor to SDF-1␣, CXCR4, is expressed in almost all CNS cell types.…”

Section: Introductionmentioning

confidence: 99%

SDF-1 overexpression by mesenchymal stem cells enhances GAP-43-positive axonal growth following spinal cord injury

Stewart

Matyas

Welchko

et al. 2017

RNN

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Abstract.Purpose: Utilizing genetic overexpression of trophic molecules in cell populations has been a promising strategy to develop cell replacement therapies for spinal cord injury (SCI). Over-expressing the chemokine, stromal derived factor-1 (SDF-1␣), which has chemotactic effects on many cells of the nervous system, offers a promising strategy to promote axonal regrowth following SCI. The purpose of this study was to explore the effects of human SDF-1␣, when overexpressed by mesenchymal stem cells (MSCs), on axonal growth and motor behavior in a contusive rat model of SCI. Methods: Using a transwell migration assay, the paracrine effects of MSCs, which were engineered to secrete human SDF-1␣ (SDF-1-MSCs), were assessed on cultured neural stem cells (NSCs). For in vivo analyses, the SDF-1-MSCs, unaltered MSCs, or Hanks Buffered Saline Solution (vehicle) were injected into the lesion epicenter of rats at 9-days post-SCI. Behavior was analyzed for 7-weeks post-injury, using the Basso, Beattie, and Bresnahan (BBB) scale of locomotor functions. Immunohistochemistry was performed to evaluate major histopathological outcomes, including gliosis, inflammation, white matter sparing, and cavitation. New axonal outgrowth was characterized using immunohistochemistry against the neuron specific growth-associated protein-43 (GAP-43). Results:The results of these experiments demonstrate that the overexpression of SDF-1␣ by MSCs can enhance the migration of NSCs in vitro. Although only modest functional improvements were observed following transplantation of SDF-1-MSCs, a significant reduction in cavitation surrounding the lesion, and an increased density of GAP-43-positive axons inside the SCI lesion/graft site were found. Conclusion:The results from these experiments support the potential role for utilizing SDF-1␣ as a treatment for enhancing growth and regeneration of axons after traumatic SCI. Research HighlightsMSCs were engineered to overexpress SDF-1␣. SDF-1␣ expression by MSCs enhances the migration of NSCs in vitro. SDF-1␣ expression by MSCs enhanced GAP-43 fibers within the lesion center.

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Reelin and CXCL12 regulate distinct migratory behaviors during the development of the dopaminergic system

Cited by 46 publications

References 70 publications

Caveolin-1 Regulates Genomic Action of the Glucocorticoid Receptor in Neural Stem Cells

Caveolin-1 Regulates Genomic Action of the Glucocorticoid Receptor in Neural Stem Cells

How to make a midbrain dopaminergic neuron

SDF-1 overexpression by mesenchymal stem cells enhances GAP-43-positive axonal growth following spinal cord injury

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