Phosphatidylcholine Biosynthesis during Neuronal Differentiation and Its Role in Cell Fate Determination

Abstract

Neuronal differentiation is characterized by neuritogenesis and neurite outgrowth, processes that are dependent on membrane biosynthesis. Thus, the production of phosphatidylcholine (PtdCho), the major membrane phospholipid, should be stimulated during neuronal differentiation. We demonstrate that during retinoic acid (RA)-induced differentiation of Neuro-2a cells, PtdCho synthesis was promoted by an ordered and sequential activation of choline kinase ␣ (CK␣) and choline cytidylyltransferase ␣ (CCT␣). Early after RA stimulation, the increase in PtdCho synthesis is mainly governed by the biochemical activation of CCT␣. Later, the transcription of CK␣-and CCT␣-encoding genes was induced. Both PtdCho biosynthesis and neuronal differentiation are dependent on ERK activation. A novel mechanism is proposed by which PtdCho biosynthesis is coordinated during neuronal differentiation. Enforced expression of either CK␣ or CCT␣ increased the rate of synthesis and the amount of PtdCho, and these cells initiated differentiation without RA stimulation, as evidenced by cell morphology and the expression of genes associated with neuritogenesis. The differentiation resulting from enforced expression of CCT␣ or CK␣ was dependent on persistent ERK activation. These results indicate that elevated PtdCho synthesis could mimic the RA signals and thus determine neuronal cell fate. Moreover, they could explain the key role that PtdCho plays during neuronal regeneration.

Prolyl Endopeptidase Is Involved in Cellular Signalling in Human Neuroblastoma SH-SY5Y Cells

“…ERK1/2 are kinases of the MAPK family involved in the regulation of many cellular processes, especially in cell proliferation and differentiation [23] . It has also been reported that RA switches on a genetic program involving ERK1/2 activation [24] . We measured ERK1/2 phosphorylation ratios at DIV5 and DIV9 in SH-SY5Y cells under control conditions, after induction of differentiation by RA and after PREP inhibition with 10 M JTP-4819 ( fig.…”

Carnosine Protects Against the Neurotoxic Effects of a Serotonin-Derived Melanoid

“…5b). Differentiation coincides with increased production of phosphatidylcholine [27] due to the increased surface area that is needed to meet the physical demands of concavity that is associated with neuritic growth. We observed that neuritic processes were preferentially affected by SDM (Fig.…”

Daily rhythms of glycerophospholipid synthesis in fibroblast cultures involve differential enzyme contributions

“…The lowest levels for ChoK ␣ were recorded at 28 h after serum stimulation, and the enzyme activity displayed a delayed profi le across time, likely refl ecting the time required for translation. Strikingly, ChoK has been shown to be strongly expressed in tumor cells ( 36 ), and although this enzyme is not the rate-limiting enzyme in PC synthesis, it has been proposed to function as a key regulatory enzyme ( 27,32,33 ) that seems to be tightly regulated in a circadian manner. Our results suggest that this enzyme may temporally control the biosynthesis of PC in synchronized cells.…”

“…However, it has been demonstrated that the availability of diacylglycerol (DAG) and regulation of ChoK also infl uence PC biosynthesis ( 27,32,33 ). In most mammals, there are two genes encoding for ChoK: Chka codes for ChoK ␣ 1/2 and Chkb codes for ChoK ␤ ( 34,35 ).…”