NM  Vol.2 No.2 , June 2011
Fas Receptor Modulates Lineage Commitment and Stemness of Mouse Neural Stem Cells
Abstract: Although transplanted neural stem/progenitor cells (NPCs) can ameliorate disease course in animal models of central nervous system inflammatory and neurodegenerative diseases, little is known about the regulation of NPC differentiation and proliferation. The Fas receptor, a member of the tumor necrosis factor (TNF) superfamily, has recently been shown to be important in NPC survival and immunoregulatory functions. We were interested in further investigating this system utilizing NPCs isolated from Fas-deficient (lpr) mutant mice. We found that lpr NPCs have increased survival and decreased proliferation. Additionally, RT-qPCR, confocal microscopy, and flow cytometry surface staining reveal that lpr NPCs have a significantly more robust differentiation to neuronal and oligoprogenitor cell lineages as compared to wild-type (wt) NPCs. These effects correlated with an upregulation of three of the major fate specification modulators in lpr NPCs: sonic hedgehog (Shh), slit homolog 2 (Slit2), and noggin. These data indicate Fas plays an important role in determining the stemness and differentiation fate of NPCs. Additionally, our research reveals a novel connection between Fas and major modulators of NPC differentiation – Shh, Noggin, and Slit2. This is the first indication of a possible link between Fas and these particular signaling molecules that control neuronal fate specification. Therefore, our results suggest Fas is a novel target for controlling the development of neurons versus mature oligodendrocytes.
Cite this paper: nullJ. Knight, C. Hackett, J. Solty and Y. Mao-Draayer, "Fas Receptor Modulates Lineage Commitment and Stemness of Mouse Neural Stem Cells," Neuroscience and Medicine, Vol. 2 No. 2, 2011, pp. 132-141. doi: 10.4236/nm.2011.22019.

[1]   Pluchino S, Martino G: The therapeutic use of stem cells for myelin repair in autoimmune demyelinating disorders. J Neurol Sci 2005, 233(1-2):117-119.

[2]   Martino G, Pluchino S: The therapeutic potential of neural stem cells. Nat Rev Neurosci 2006, 7(5):395-406.

[3]   Pluchino S, Zanotti L, Rossi B, Brambilla E, Ottoboni L, Salani G, Martinello M, Cattalini A, Bergami A, Furlan R et al: Neurosphere-derived multipotent precursors promote neuroprotection by an immunomodulatory mechanism. Nature 2005, 436(7048):266-271.

[4]   Nagata S, Golstein P: The Fas death factor. Science 1995, 267(5203):1449-1456.

[5]   van Landeghem FKH, Felderhoff-Mueser U, Moysich A, Stadelmann C, Obladen M, Brück W, Bührer C: Fas (CD95/Apo-1)/Fas ligand expression in neonates with pontosubicular neuron necrosis. Pediatr Res 2002, 51(2):129-135.

[6]   Nat R, Radu E, Regalia T, Popescu LM: Apoptosis in human embryo development: 3. Fas-induced apoptosis in brain primary cultures. J Cell Mol Med 2001, 5(4):417-428.

[7]   Knight J, Scharf E, Mao-Draayer Y: Fas activation increases neural progenitor cell survival. J Neurosci Res 2009.

[8]   Corsini NS, Sancho-Martinez I, Laudenklos S, Glagow D, Kumar S, Letellier E, Koch P, Teodorczyk M, Kleber S, Klussmann S et al: The death receptor CD95 activates adult neural stem cells for working memory formation and brain repair. Cell Stem Cell 2009, 5(2):178-190.

[9]   Desbarats J, Birge RB, Mimouni-Rongy M, Weinstein DE, Palerme J-S, Newell MK: Fas engagement induces neurite growth through ERK activation and p35 upregulation. Nat Cell Biol 2003, 5(2):118-125.

[10]   Pluchino S, Muzio L, Imitola J, Deleidi M, Alfaro-Cervello C, Salani G, Porcheri C, Brambilla E, Cavasinni F, Bergamaschi A et al: Persistent inflammation alters the function of the endogenous brain stem cell compartment. Brain 2008, 131(Pt 10):2564-2578.

[11]   Franklin RJM, Ffrench-Constant C: Remyelination in the CNS: from biology to therapy. Nat Rev Neurosci 2008, 9(11):839-855.

[12]   Stangel M: Neuroprotection and neuroregeneration in multiple sclerosis. J Neurol 2008, 255 Suppl 6:77-81.

[13]   Blakemore WF: Regeneration and repair in multiple sclerosis: the view of experimental pathology. J Neurol Sci 2008, 265(1-2):1-4.

[14]   Kobayashi T, Mizuno H, Imayoshi I, Furusawa C, Shirahige K, Kageyama R: The cyclic gene Hes1 contributes to diverse differentiation responses of embryonic stem cells. Genes Dev 2009, 23(16):1870-1875.

[15]   Patel K, Nash JA, Itoh A, Liu Z, Sundaresan V, Pini A: Slit proteins are not dominant chemorepellents for olfactory tract and spinal motor axons. Development 2001, 128(24):5031-5037.

[16]   Lin L, Isacson O: Axonal growth regulation of fetal and embryonic stem cell-derived dopaminergic neurons by Netrin-1 and Slits. Stem Cells 2006, 24(11):2504-2513.

[17]   Wu W, Wong K, Chen J, Jiang Z, Dupuis S, Wu JY, Rao Y: Directional guidance of neuronal migration in the olfactory system by the protein Slit. Nature 1999, 400(6742):331-336.

[18]   Zhu G, Mehler MF, Zhao J, Yu Yung S, Kessler JA: Sonic hedgehog and BMP2 exert opposing actions on proliferation and differentiation of embryonic neural progenitor cells. Dev Biol 1999, 215(1):118-129.

[19]   Palma V, Lim DA, Dahmane N, Sánchez P, Brionne TC, Herzberg CD, Gitton Y, Carleton A, Alvarez-Buylla A, Ruiz i Altaba A: Sonic hedgehog controls stem cell behavior in the postnatal and adult brain. Development 2005, 132(2):335-344.