TY - JOUR
T1 - Differential effects of three inhibitors of glycosphingolipid biosynthesis on neuronal differentiation of embryonal carcinoma stem cells
AU - Liour, Sean S.
AU - Yu, Robert K.
N1 - Funding Information:
This work was supported by a USPHS grant NS11853 and a grant from the Childrens Medical Research Foundation. The authors gratefully acknowledge the samples of D-PDMP from Dr. James Shayman, University of Michigan, Ann Arbor, MI. The authors would also like to thank Dr. Erhard Bieberich’s helpful discussion and Dr. Stacey Kraemer’s editing of the manuscript.
Copyright:
Copyright 2008 Elsevier B.V., All rights reserved.
PY - 2002/11/1
Y1 - 2002/11/1
N2 - Gangliosides have been implicated in having important roles in neural development. It has been shown that disruption of ganglioside biosynthesis inhibits neurite outgrowth. However, many contradictory results have been reported. The inconsistency of these reports may result from the differential use of neuronal cell lines and inhibitors for ganglioside biosynthesis. In order to clarify the inconsistency in these studies, we utilized an in vitro neuronal differentiation model using an embryonic caricinoma (EC) stem cell line to elucidate the relationship between ganglioside expression and neural development. These cells were exposed to three different inhibitors of glucosylceramide synthase, the first enzyme committed for the biosynthesis of most of the brain gangliosides. All three inhibitors, D-threo-1-phenyl-2-decanoylamino-3-morphlino-1-propanol (D-PDMP), D-threo-1-phenyl-2-palmitoylamino-3-pyrrolidino-1-propanol (D-PPPP), and N-butydeoxynojirimycin (NB-DNJ) can inhibit greater than 90% of ganglioside biosynthesis at certain concentrations, respectively. D-PDMP significantly slowed down cellular proliferation in undifferentiated P19 EC cells, inhibited neurite outgrowth, and eventually caused cell death in differentiated cells. However. no retardation in cell growth, neuronal differentiation, and neurite outgrowth was observed in cultures treated with D-PPPP or NB-DNJ despite the depletion of gangliosides. These results indicate that the effect of D-PDMP on cellular proliferation, neurite outgrowth, and survival of differentiated cells is independent of the inhibition of ganglioside biosynthesis.
AB - Gangliosides have been implicated in having important roles in neural development. It has been shown that disruption of ganglioside biosynthesis inhibits neurite outgrowth. However, many contradictory results have been reported. The inconsistency of these reports may result from the differential use of neuronal cell lines and inhibitors for ganglioside biosynthesis. In order to clarify the inconsistency in these studies, we utilized an in vitro neuronal differentiation model using an embryonic caricinoma (EC) stem cell line to elucidate the relationship between ganglioside expression and neural development. These cells were exposed to three different inhibitors of glucosylceramide synthase, the first enzyme committed for the biosynthesis of most of the brain gangliosides. All three inhibitors, D-threo-1-phenyl-2-decanoylamino-3-morphlino-1-propanol (D-PDMP), D-threo-1-phenyl-2-palmitoylamino-3-pyrrolidino-1-propanol (D-PPPP), and N-butydeoxynojirimycin (NB-DNJ) can inhibit greater than 90% of ganglioside biosynthesis at certain concentrations, respectively. D-PDMP significantly slowed down cellular proliferation in undifferentiated P19 EC cells, inhibited neurite outgrowth, and eventually caused cell death in differentiated cells. However. no retardation in cell growth, neuronal differentiation, and neurite outgrowth was observed in cultures treated with D-PPPP or NB-DNJ despite the depletion of gangliosides. These results indicate that the effect of D-PDMP on cellular proliferation, neurite outgrowth, and survival of differentiated cells is independent of the inhibition of ganglioside biosynthesis.
KW - Ganglioside biosynthesis
KW - Glucosylceramide synthase
KW - Neuronal differentiation
KW - Stem cells
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U2 - 10.1023/A:1021652506370
DO - 10.1023/A:1021652506370
M3 - Article
C2 - 12512955
AN - SCOPUS:0036865666
SN - 0364-3190
VL - 27
SP - 1507
EP - 1512
JO - Neurochemical Research
JF - Neurochemical Research
IS - 11
ER -