Abstract
Phospholipase D1 (PLD1) is generally accepted as playing an important role in the regulation of multiple cell functions, such as cell growth, survival, differentiation, membrane trafficking, and cytoskeletal organization. Recent findings suggest that PLD1 also plays an important role in the regulation of neuronal differentiation of neuronal cells. Moreover, PLD1-mediated signaling molecules dynamically regulate the neuronal differentiation of neural stem cells (NSCs). Rho family GTPases and Ca2+-dependent signaling, in particular, are closely involved in PLD1-mediated neuronal differentiation of NSCs. Moreover, PLD1 has a significant effect on the neurogenesis of NSCs via the regulation of SHP-1/STAT3 activation. Therefore, PLD1 has now attracted significant attention as an essential neuronal signaling molecule in the nervous system. In the current review, we summarize recent findings on the regulation of PLD1 in neuronal differentiation and discuss the potential role of PLD1 in the neurogenesis of NSCs.
Similar content being viewed by others
Avoid common mistakes on your manuscript.
Introduction
Overview of NSCs
Neural stem cells (NSCs) are multipotent cells that are capable of proliferation and self-renewal, which can differentiate into all types of neural cells, namely neurons, astrocytes, and oligodendrocytes (Miller and Gauthier 2007). In 1992, NSCs were first isolated from the adult striatal tissue, including the subventricular zone and adult mice brain tissue (Reynolds and Weiss 1992). Following the discovery of NSCs, significant advances have been made in our understanding about its localization, development, persistence, properties, and potential in the central nervous system (Xu et al. 2017). Multipotent NSCs can be isolated and cultured from primary cortical or hippocampal cultures after passage in the presence of mitogenic growth factors (Gage et al. 1995), such as epidermal growth factor and basic fibroblast growth factor (bFGF). Mitogenic growth factors are important for NSCs proliferation (Mudo et al. 2009) and the maintenance of its undifferentiated state (Vescovi et al. 1993). The coordinated action of multiple signals acting on embryonic NSCs gives rise to the vast diversity of neuronal and glial populations that populate the mature brain (Xu et al. 2017). Specific transcriptional factors are important for the differentiation of NSCs into the major neural cell types (Fig. 1). NSCs also play a crucial role in animals. In addition to supplying neurons to the olfactory bulb in mice, NSCs are also important for learning and hippocampal plasticity in adult mice (Paspala et al. 2011). Moreover, since the activation of NSCs or their transplantation into areas of central nervous system injury can lead to regeneration in animal models and humans, its putative clinical application has attracted considerable interest.
PLD Structure
Phospholipase D (PLD) is a ubiquitous enzyme that hydrolyzes phosphatidylcholine (PC) to yield phosphatidic acid (PA) and free choline. In the presence of primary alcohols, such as ethanol and 1-butanol, PLD preferentially catalyzes the transphosphatidylation reaction, rather than the hydrolytic reaction, which produces phosphatidyl alcohols at the expense of PA production (Fig. 2a) (Kanaho et al. 2009). Two major PLD isozymes, i.e., PLD1 and PLD2, have been well identified in mammalian cells (Jenkins and Frohman 2005). PLD1 is a 1074-amino acid protein with an apparent molecular weight of 120 kDa. PLD2 is a 933-amino acid protein with an apparent molecular weight of 106 kDa. Mammalian PLD1 and PLD2 both contain two HKD motifs (HxKxxxxD sequence, histidine “H,” any amino acid “x,” lysine “K,” and aspartic acid “D”), which are critical for enzymatic catalysis, both in vitro and in vivo, as evidenced by the observation that point mutations in the motif disrupt PLD activity (Sung et al. 1997). Other highly conserved domains of the PLD isozymes include the phox (PX), pleckstrin homology (PH), and PI4,5P2 binding domains, which markedly activates PLD2 and are required for small GTPase ARF stimulation of PLD1 (Exton 2002; Kanaho et al. 2009). Although the PH domain appears to regulate the PLD association with lipid rafts facilitating the recovery of the enzyme to endosomes (Du et al. 2003), it is not required for PLD activity (Sung et al. 1999). The PX domain mediates protein-protein interactions or preferentially binds PI3,4,5P3 (Xu et al. 2001). Finally, PLD1 has a conserved loop domain, which is not found PLD2. This loop domain is involved in the auto inhibition of PLD1, since its deletion from PLD1 results in high basal activity (Fig. 2b).
PLD Functions
Numerous reports suggest that PLD1 contributes to various cellular mechanisms, including inflammation, tumor cell invasion and metastasis, lipid metabolism, and neural development (Bae et al. 2014; Brown et al. 2017; Bruntz et al. 2014). Therefore, PLD1 have emerged as drug targets for many diseases such as infectious diseases, cancer, cardio-vascular diseases, and neurodegenerative diseases (Brown et al. 2017; Eftekharian et al. 2017). PLD1 is found throughout the cell, particularly, in the perinuclear region, Golgi complex, and early endosomes in non-stimulated cells. Further, it is relocated to the plasma membrane upon stimulation. Increased expression of PLD1, its subcellular localization and altered catalytic activity have essential roles in cell proliferation, differentiation, vesicle trafficking, and cytoskeleton rearrangement in neuron (Brito de Souza et al. 2014; Luo et al. 2017). PLD1 is expressed in many functionally diverse brain areas, including the cerebral cortex, hippocampus, brain stem, spinal cord, and olfactory bulb (Lee et al. 2000). Recent studies have reported that the signal-dependent activation of PLD1 is important for neuronal differentiation in NSCs (Park et al. 2015, 2017; Yoon et al. 2005, 2006). PLD2 is almost exclusively found in the light membrane “lipid raft” fraction of the plasma membrane (Gomez-Cambronero and Keire 1998). PLD2 can be activated in intact cells by a variety of agonists and tyrosine kinases. Further, it can be regulated by small GTPases and certain PKC family members (Gomez-Cambronero 2014). PLD2 promotes neurite outgrowth in PC12 cells and functions as a downstream signaling effector of extracellular signal-regulated kinases in the nerve growth factor (NGF) signaling pathway. In PC12 cells and cerebellar granule neurons, this pathway is activated by NGF and neuronal cell adhesion molecule L1 (Watanabe et al. 2004; Yun et al. 2006). Therefore, both PLD1 and PLD2 appear to influence neurite outgrowth. However, the role of PLD2 in neuronal differentiation of NSCs has not yet been elucidated. Therefore, this review focused on the role of PLD1 in neuronal differentiation and described its potential role in the neurogenesis of NSCs.
Role of PLD1 in Neuronal Differentiation of NSCs
In HiB5 cells, the activation of PLD contributes to neuronal differentiation via neurogenic platelet-derived growth factor (PDGF) (Sung et al. 2001). Further, NGF-induced PLD1 expression mediates neuronal differentiation of PC12 cells (Ammar et al. 2013; Min et al. 2001). PLD1 is also implicated in the bFGF-induced neurite outgrowth of H19-7 cells (Klein 2005; Yoon et al. 2012). In addition, PLD1 corrected the impaired neurite outgrowth capacity of familial Alzheimer’s disease mutant neurons (Cai et al. 2006). Thus, PLD1 is a key molecule in neuronal differentiation, especially neurite outgrowth. Yoon et al. (Yoon et al. 2005) reported for the first time that PLD1 is required for neurite outgrowth during neuronal differentiation of NSCs. Since then, PLD1-mediated signaling pathways have been identified in neuronal differentiation of NSCs. Herein, we summarize the PLD1-mediated signaling molecules involved in the neuronal differentiation of NSCs.
PLD1 and Rho Family GTPases in Neuronal Differentiation of NSCs
During brain development, each neuron develops into a single axon and multiple neurites, which then eventually form synapses (Elston and Fujita 2014; Huang et al. 2017). To ensure precise neuronal connectivity, neurons are derived from the coordination of multiple developmental steps, including axon growth, branching, guidance, and synapse formation (Huang et al. 2017). Cytoskeleton rearrangement is required for the dynamics of neuronal morphology formation. The Rho family GTPases, of which RhoA, Cdc42, and Rac1 are best characterized, act as significant modulators of cytoskeleton rearrangement (Threadgill et al. 1997). The Rho family GTPases serves as a molecular switch by converting from an inactive GDP-bound state to an active GTP-bound state. Once activated, they can interact with their specific effectors. Recent reports suggest that RhoA, Rac1, and Cdc42 play a central role in dendritic development. Further, the differential activation of Rho-related GTPases contributes to the generation of morphological diversity in the developing cortex (Threadgill et al. 1997). Rac1 and Cdc42 promote neurite initiation and outgrowth (Daniels et al. 1998). Conversely, RhoA activation antagonizes neurite formation and causes neurite retraction. Thus, the regulation of Rho family GTPases is crucial for guiding downstream biological reactions, such as axon growth or retraction, and synapse maturation during neuronal development.
The Rho family GTPases are important regulators of PLD activity (Powner and Wakelam 2002). PLD1 activity is regulated particularly by interactions with small GTPases that belong to the ARF and Rho families (Powner and Wakelam 2002; Rudge and Wakelam 2009). The transfection of RhoA, Cdc42, or Rac1 can activate PLD1 (Powner and Wakelam 2002; Yoon et al. 2006), which has been implicated in the regulation of the actin cytoskeleton (Rudge and Wakelam 2009). PLD1 controls many physiological functions, such as cell migration and neuronal axon formation, via this regulatory action. In NSCs, the expression levels of Cdc42 and RhoA were increased during neuronal differentiation, and PLD1 and Cdc42 were co-localized in neurites, while RhoA was localized in the cytosol (Yoon et al. 2006). Further, Cdc42 was bound to PLD1 during differentiation, and dominant-negative Cdc42 (Cdc42N17) decreased PLD activity and neurite outgrowth. Conversely, constitutively active Cdc42 (Cdc42V12) increased both PLD activity and neurite outgrowth, suggesting that the association between Cdc42 and PLD1 is important for the activation of PLD1 and neurite outgrowth in NSCs. Moreover, a dominant-negative Rac1 (Rac N17) mutant inhibited PLD1-induced Bcl-2 expression. Bcl-2 expression, however, was not altered by DN-Cdc42 (Cdc42 N17) or DN-Rho (Rho V19) during neuronal differentiation of NSCs (Park et al. 2015). Therefore, the interplay between PLD1 and Rho family GTPases has an important role in the neuronal differentiation of NSCs.
PLD1 and Bcl-2 Expression in Neuronal Differentiation of NSCs
Bcl-2 is a well-known anti-apoptotic protein that prevents the release of apoptogenic factors, such as cytochrome c and second mitochondrial-derived activator of caspase, which was originally found to be overexpressed in B cell lymphoma (Gross et al. 1999). Bcl-2 serves as a critical regulator of pathways involved in apoptosis and inhibits cell death (Liu et al. 2013). Proteins of the Bcl-2 family influence neuronal apoptosis and cell differentiation and a reduction in the ability of neurons to extend neurites in Bcl-2-deficient embryos (Chen et al. 1997; Yoon et al. 2012). Bcl-2 is critical for the neuronal commitment of mouse embryonic stem cells (Trouillas et al. 2008). Moreover, the anti-apoptotic role of Bcl-2 has been well identified in previous studies, in which anti-apoptotic gene modifications have had beneficial effects on the neural differentiation of neural progenitors and NSCs (Esdar et al. 2001; Lee et al. 2009). In vivo studies also indicated that the overexpression of Bcl-2 enhanced retinal axon regeneration after optic-tract transaction (Chen et al. 1997) and increased axonal growth of transplanted fetal dopaminergic neurons in the rat striatum (Holm et al. 2001).
Recent studies have demonstrated that Bcl-2 is implicated in PLD1-mediated neuronal differentiation. PLD1 is known to regulate Bcl-2 expression in various cells (Cho et al. 2008, 2011; Choi and Han 2012). For instance, PLD1 regulates Bcl-2 expression via the JNK/STAT3 pathway, which leads to neuronal cell differentiation of H19-7 cells (Yoon et al. 2012). A recent study also demonstrated that PLD1 increased Bcl-2 expression and promoted Bcl-2-mediated signaling in NSCs (Park et al. 2015). More specifically, PLD1 is regulated by PLCγ/PKCα activation and promotes Bcl-2 expression, via the PA/AA/PGE2/EP4/PKA/p38 MAPK pathway during neuronal differentiation. These results suggest that PLD1-mediated Bcl-2 expression affects the neuronal differentiation of NSCs.
PLD1 and Ca2+-Dependent Signaling in Neuronal Differentiation of NSCs
The development of the nervous system occurs through a series of well-organized steps in the proliferation of NSCs, its migration over considerable distances from the germinal centers to their destinations, and ultimately their differentiation into billions of neurons and glia, which populate the brain (Toth et al. 2016). In these processes, Ca2+ signaling is essential for the developing brain (Zheng and Poo 2007). Increased Ca2+ levels regulate PKCα activation and translocation to the membrane from the cytosol in various processes (Boncoeur et al. 2013; Champion and Kass 2004). PKCα regulates Ca2+-dependent differentiation in several cell lines and primary cells and plays an essential role in synaptic plasticity by raising intracellular Ca2+ levels (Kopach et al. 2013; Park et al. 2015). PLD catalyzes the hydrolysis of PC to PA and choline (Exton 2002). PA itself acts as a cellular messenger or is further transformed by PA phosphohydrolase into DAG, which is essential for the activation of PKC (Zhao et al. 2007). The activation and phosphorylation of PLD1 is regulated by PKCα, with a similar interrelationship between PLD and PKC isoforms seen in a variety of cell types (Kim et al. 2005; Park et al. 2015). Recent studies revealed that increased intracellular Ca2+ affects PKCα activation and neurite outgrowth in NSCs (Park et al. 2015, 2017). In addition, a PKCα specific inhibitor, RO320432, reduced the activation of PLD1 and affected PLD1 signaling during differentiation in NSCs (Park et al. 2015, 2017). Moreover, intracellular Ca2+ promotes neurogenesis by translocating PKCα to the membrane through making complex with hippocalcin (HPCA). And then PKCα is activated by direct binding to phosphoinositide-dependent protein kinase 1 (PDK1) in NSCs. PDK1 signals upstream of PKCα trigger neurite outgrowth leading to increased expressions of Nt3, Nt45, Bdnf, and Neuro D in NSCs (Park et al. 2017).
Another important Ca2+ signaling factor, phospholipase C (PLCγ), also affects PLD1 signaling in several cells (Park et al. 2009, 2015; Yoon et al. 2012). When treated with some growth factors, PLCγ is phosphorylated and generates DAG and inositol 1,4,5-triphosphate (IP3), which in turn activates PKCα, consequently increasing intracellular Ca2+ (Hall et al. 1996; Oh et al. 2008). Recent studies demonstrated that PLCγ signaling elevates the intracellular Ca2+ concentration and regulates neocortical neuronal progenitor migration and neuronal differentiation (Lundgren et al. 2012; Park et al. 2015). Moreover, the inhibition of PLCγ using a specific inhibitor, U73122, or blocking intracellular [Ca2+]i with BAPTA-AM, reduced the phosphorylation and activation of PKCα during neuronal differentiation of NSCs (Park et al. 2015). Furthermore, U73122 or BAPTA-AM inhibited PLD1 activity and neuronal differentiation in NSCs (Park et al. 2015). Taken together, these results suggest that intracellular Ca2+ signal molecules, including PLCγ, PKCα, and PDK1, regulate PLD1-mediated neuronal differentiation in NSCs.
HPCA is a high-affinity Ca2+-binding protein, which is restricted to the CNS and most abundant in pyramidal cells of the CA1 region in the hippocampus (Kobayashi et al. 2005). During brain development the expression of HPCA sharply increases concurrently with synapse formation (Saitoh et al. 1994). HPCA belongs to the family of EF-hand-containing neuronal Ca2+ sensor proteins, which possess a Ca2+/myristoyl switch that allows its translocation to the membrane, in response to increased cytosolic Ca2+ concentrations (Oh et al. 2008; Park et al. 2017). HPCA exerts a neuroprotective action by blocking the formation of Ca2+-induced cell death stimuli (Masuo et al. 2007). Further, infusion of mutant Hpca lacking Ca2+-binding sites prevents long-term depression in hippocampal neurons (Jo et al. 2010). Since HPCA has a crucial role in Ca2+-mediated neuronal activity in the brain, it is possible that HPCA is implicated in neuronal differentiation of NSCs. HPCA is also regulated by a Ca2+-mediated PLD1 signaling pathway (Oh et al. 2008; Park et al. 2017). It also induces the expression of neuro-D, leading to neurite outgrowth during differentiation in H19-7 cells (Oh et al. 2008). A recent study demonstrated that the expression of nerve growth factors, such as NT-3, NT-45, and BDNF, depended on Ca2+ binding and the myristoylation of HPCA during the neuronal differentiation of NSCs (Park et al. 2017). Interestingly, HPCA directly binds to PKCα, which facilitates the PKCα-regulated kinase cascade; PKCα-dependent PLD1 activation is required for neurite outgrowth. Moreover, PLD1 and HPCA were even co-localized on embryonic day 14 (E14) in the rat cerebral neocortex, and HPCA-dependent PLD1 activation was required for neuronal differentiation of NSCs. Finally, their collaboration greatly influenced the neurogenesis of NSCs (Park et al. 2017).
PLD1 as an Accelerator in Neurogenesis of NSCs
Neurogenesis is the transition of proliferative and multipotent NSCs to fully differentiated neurons. It occurs in multiple brain areas, including the neocortex, piriform cortex, amygdala, substantia nigra, striatum, and hypothalamus (Iannitelli et al. 2017). Neurogenesis is the process by which neurons are generated from neural stem cells and progenitor cells. It precedes gliogenesis throughout the nervous system, and a single progenitor can give rise to both neurons and astrocytes (Bayer et al. 1991). Neurogenesis is tightly controlled owing to its critical importance in proper physiological function, and the multiple signals controlling the growth and directionality of the relevant cell fate decision (Sun et al. 2001). To promote neurogenesis, proneural basic helix-loop-helix (bHLH) transcription factors, such as neurogenin-1 and Mash-1, not only drive neurogenesis by activating the expression of a cascade of neuronal genes (Frohman et al. 1999) but also through inhibiting glial gene expression (Urban and Guillemot 2014). However, some neurogenic factors can regulate both these processes, depending on the concentration of proneural genes. For example, although bone morphogenetic proteins promote neurogenesis in progenitor cells that express high levels of neurogenin-1, it promotes gliogenesis in progenitor cells that have a low level of neurogenin-1 expression (Morrison 2001). Thus, embryonic neurogenesis is tightly linked to cell fate specification. Moreover, according to recent studies, the molecular and genetic factors influencing neurogenesis notably include the Notch pathway; many genes have been linked to Notch pathway regulation (Kageyama et al. 2008; Rash et al. 2011).
How Does PLD1 Promote Neurogenesis in NSCs?
Over the past year several regulatory mechanisms, including the promotion of neurogenesis by proneural bHLH genes and the instruction of gliogenesis by signal transducers and activators of transcription 3 (STAT3) in a neurogenic capacity of NSCs in culture, have been identified (Kang et al. 2016; Park et al. 2017). STAT3 is an important transcription factor that regulates glial fibrillary acidic protein (GFAP) expression. Further, the DNA binding of STAT3 was affected by the phosphorylation of the Ser727 or/and Tyr 705 site (Yokogami et al. 2000). STAT3 binds to different domains of CBP/p300 and the STAT/p300/Smad complex, acting at the STAT-binding element in the astrocyte-specific GFAP promoter, which is particularly effective at inducing astrocyte differentiation in NSCs (Nakashima et al. 1999). SH2-domain-containing tyrosine phosphatase-1 (SHP-1) negatively regulates STAT3 signaling through the direct de-phosphorylation of STAT3 (Tyr 705). Importantly, this SHP-1-dependent STAT3-inhibitory mechanism is closely involved in PLD1-directed neurogenesis in NSCs. PLD-derived PA interacts with and inhibits SHP-1 activity (Frank et al. 1999). Exogenously added PA induced phosphorylation of SHP-1 and de-phosphorylation of STAT3 (Tyr 705) in a dose-dependent manner in NSCs. Moreover, PLD1 knockdown inhibited SHP-1 activity and affected the de-phosphorylation of STAT3 (Tyr 705). Thus, PLD1 promotes neurogenesis and suppresses gliogenesis by controlling the activation of SHP-1/STAT3 in NSCs. Therefore, PLD1/PA/SHP-1/STAT3 signaling is an important pathway in embryonic brain neurogenesis.
Conclusions
To summarize the findings presented thus far, PLD1 is critical for neuronal differentiation, which is regulated by multiple signals, contributing to the neuron-to-astrocyte switch in NSCs from the rat E14 cortex (Fig. 3). Therefore, PLD1 may have a positive role in neuronal differentiation of NSCs. Conversely, however, it has also been reported that PLD1 plays a negative role in neuronal differentiation, especially in the dendritic branching of cultured hippocampal neurons from rat E18 (Zhu et al. 2012). In culture, progenitor cells isolated at different embryonic stages behave in a manner that mimics the normal process of development. Progenitor cells from rat E14 cortex (at the peak of neurogenesis) primarily give rise to neurons and dividing precursor cells. In contrast, E18 progenitor cells immediately give rise to astrocytes (Sun et al. 2001). These studies have demonstrated that the role of PLD1 may be reversed depending on the age and location of the stem cell embryo. In this regard, we should now consider the study of how PLD1 regulates neurogenesis according to the age and location of the embryo. Addressing this will provide us with insights into the differentiation mechanisms of neural stem cells following the developmental stages of the brain. Further, it may also help us in the application of neural stem cells to repair the damaged or degenerative nervous system.
References
Ammar MR, Humeau Y, Hanauer A, Nieswandt B, Bader MF, Vitale N (2013) The Coffin-Lowry syndrome-associated protein RSK2 regulates neurite outgrowth through phosphorylation of phospholipase D1 (PLD1) and synthesis of phosphatidic acid. J Neurosci 33:19470–19479. https://doi.org/10.1523/JNEUROSCI.2283-13.2013
Bae EJ, Lee HJ, Jang YH, Michael S, Masliah E, Min DS, Lee SJ (2014) Phospholipase D1 regulates autophagic flux and clearance of alpha-synuclein aggregates. Cell Death Differ 21:1132–1141. https://doi.org/10.1038/cdd.2014.30
Bayer SA, Altman J, Russo RJ, Dai XF, Simmons JA (1991) Cell migration in the rat embryonic neocortex. J Comp Neurol 307:499–516. https://doi.org/10.1002/cne.903070312
Boncoeur E, Bouvet GF, Migneault F, Tardif V, Ferraro P, Radzioch D, de Sanctis JB, Eidelman D, Govindaraju K, Dagenais A, Berthiaume Y (2013) Induction of nitric oxide synthase expression by lipopolysaccharide is mediated by calcium-dependent PKCalpha-beta1 in alveolar epithelial cells. Am J Physiol Lung Cell Mol Physiol 305:L175–L184. https://doi.org/10.1152/ajplung.00295.2012
Brito de Souza L, Pinto da Silva LL, Jamur MC, Oliver C (2014) Phospholipase D is involved in the formation of Golgi associated clathrin coated vesicles in human parotid duct cells. PLoS One 9:e91868. https://doi.org/10.1371/journal.pone.0091868
Brown HA, Thomas PG, Lindsley CW (2017) Targeting phospholipase D in cancer, infection and neurodegenerative disorders. Nat Rev Drug Discov 16:351–367. https://doi.org/10.1038/nrd.2016.252
Bruntz RC, Lindsley CW, Brown HA (2014) Phospholipase D signaling pathways and phosphatidic acid as therapeutic targets in cancer. Pharmacol Rev 66:1033–1079. https://doi.org/10.1124/pr.114.009217
Cai D, Zhong M, Wang R, Netzer WJ, Shields D, Zheng H, Sisodia SS, Foster DA, Gorelick FS, Xu H, Greengard P (2006) Phospholipase D1 corrects impaired betaAPP trafficking and neurite outgrowth in familial Alzheimer’s disease-linked presenilin-1 mutant neurons. Proc Natl Acad Sci U S A 103:1936–1940. https://doi.org/10.1073/pnas.0510710103
Champion HC, Kass DA (2004) Calcium handler mishandles heart. Nat Med 10:239–240. https://doi.org/10.1038/nm0304-239
Chen DF, Schneider GE, Martinou JC, Tonegawa S (1997) Bcl-2 promotes regeneration of severed axons in mammalian CNS. Nature 385:434–439. https://doi.org/10.1038/385434a0
Cho JH, Hong SK, Kim EY, Park SY, Park CH, Kim JM, Kwon OJ, Kwon SJ, Lee KS, Han JS (2008) Overexpression of phospholipase D suppresses taxotere-induced cell death in stomach cancer cells. Biochim Biophys Acta 1783:912–923. https://doi.org/10.1016/j.bbamcr.2007.11.019
Cho JH, Oh DY, Kim HJ, Park SY, Choi HJ, Kwon SJ, Lee KS, Han JS (2011) The TSP motif in AP180 inhibits phospholipase D1 activity resulting in increased efficacy of anticancer drug via its direct binding to carboxyl terminal of phospholipase D1. Cancer Lett 302:144–154. https://doi.org/10.1016/j.canlet.2011.01.005
Choi HJ, Han JS (2012) Overexpression of phospholipase D enhances Bcl-2 expression by activating STAT3 through independent activation of ERK and p38MAPK in HeLa cells. Biochim Biophys Acta 1823:1082–1091. https://doi.org/10.1016/j.bbamcr.2012.03.015
Daniels RH, Hall PS, Bokoch GM (1998) Membrane targeting of p21-activated kinase 1 (PAK1) induces neurite outgrowth from PC12 cells. EMBO J 17:754–764. https://doi.org/10.1093/emboj/17.3.754
Du G et al (2003) Regulation of phospholipase D1 subcellular cycling through coordination of multiple membrane association motifs. J Cell Biol 162:305–315. https://doi.org/10.1083/jcb.200302033
Eftekharian MM, Azimi T, Ghafouri-Fard S, Sayad A, Omrani MD, Sarrafzadeh S, Abbasalipourkabir R, Mazdeh M, Taheri M (2017) Phospholipase D1 expression analysis in relapsing-remitting multiple sclerosis patients. Neurol Sci 38:865–872. https://doi.org/10.1007/s10072-017-2857-1
Elston GN, Fujita I (2014) Pyramidal cell development: postnatal spinogenesis, dendritic growth, axon growth, and electrophysiology. Front Neuroanat 8:78. https://doi.org/10.3389/fnana.2014.00078
Esdar C, Milasta S, Maelicke A, Herget T (2001) Differentiation-associated apoptosis of neural stem cells is effected by Bcl-2 overexpression: impact on cell lineage determination. Eur J Cell Biol 80:539–553. https://doi.org/10.1078/0171-9335-00185
Exton JH (2002) Phospholipase D-structure, regulation and function. Rev Physiol Biochem Pharmacol 144:1–94
Frank C, Keilhack H, Opitz F, Zschornig O, Bohmer FD (1999) Binding of phosphatidic acid to the protein-tyrosine phosphatase SHP-1 as a basis for activity modulation. Biochemistry 38:11993–12002
Frohman MA, Sung TC, Morris AJ (1999) Mammalian phospholipase D structure and regulation. Biochim Biophys Acta 1439:175–186
Gage FH, Ray J, Fisher LJ (1995) Isolation, characterization, and use of stem cells from the CNS. Annu Rev Neurosci 18:159–192. https://doi.org/10.1146/annurev.ne.18.030195.001111
Gomez-Cambronero J (2014) Phosphatidic acid, phospholipase D and tumorigenesis. Adv Biol Regul 54:197–206. https://doi.org/10.1016/j.jbior.2013.08.006
Gomez-Cambronero J, Keire P (1998) Phospholipase D: a novel major player in signal transduction. Cell Signal 10:387–397
Gross A, McDonnell JM, Korsmeyer SJ (1999) BCL-2 family members and the mitochondria in apoptosis. Genes Dev 13:1899–1911
Hall H, Williams EJ, Moore SE, Walsh FS, Prochiantz A, Doherty P (1996) Inhibition of FGF-stimulated phosphatidylinositol hydrolysis and neurite outgrowth by a cell-membrane permeable phosphopeptide. Curr Biol 6:580–587
Holm KH, Cicchetti F, Bjorklund L, Boonman Z, Tandon P, Costantini LC, Deacon TW, Huang X, Chen DF, Isacson O (2001) Enhanced axonal growth from fetal human bcl-2 transgenic mouse dopamine neurons transplanted to the adult rat striatum. Neuroscience 104:397–405
Huang GH, Sun ZL, Li HJ, Feng DF (2017) Rho GTPase-activating proteins: regulators of rho GTPase activity in neuronal development and CNS diseases. Mol Cell Neurosci 80:18–31. https://doi.org/10.1016/j.mcn.2017.01.007
Iannitelli A, Quartini A, Tirassa P, Bersani G (2017) Schizophrenia and neurogenesis: a stem cell approach. Neurosci Biobehav Rev 80:414–442. https://doi.org/10.1016/j.neubiorev.2017.06.010
Jenkins GM, Frohman MA (2005) Phospholipase D: a lipid centric review. Cell Mol Life Sci 62:2305–2316. https://doi.org/10.1007/s00018-005-5195-z
Jo J, Son GH, Winters BL, Kim MJ, Whitcomb DJ, Dickinson BA, Lee YB, Futai K, Amici M, Sheng M, Collingridge GL, Cho K (2010) Muscarinic receptors induce LTD of NMDAR EPSCs via a mechanism involving hippocalcin, AP2 and PSD-95. Nat Neurosci 13:1216–1224. https://doi.org/10.1038/nn.2636
Kageyama R, Ohtsuka T, Shimojo H, Imayoshi I (2008) Dynamic Notch signaling in neural progenitor cells and a revised view of lateral inhibition. Nat Neurosci 11:1247–1251. https://doi.org/10.1038/nn.2208
Kanaho Y, Funakoshi Y, Hasegawa H (2009) Phospholipase D signalling and its involvement in neurite outgrowth. Biochim Biophys Acta 1791:898–904. https://doi.org/10.1016/j.bbalip.2009.03.010
Kang MJ, Park SY, Han JS (2016) Hippocalcin is required for astrocytic differentiation through activation of Stat3 in hippocampal neural precursor cells. Front Mol Neurosci 9:110. https://doi.org/10.3389/fnmol.2016.00110
Kim JH, Kim JH, Ohba M, Suh PG, Ryu SH (2005) Novel functions of the phospholipase D2-Phox homology domain in protein kinase Czeta activation. Mol Cell Biol 25:3194–3208. https://doi.org/10.1128/MCB.25.8.3194-3208.2005
Klein J (2005) Functions and pathophysiological roles of phospholipase D in the brain. J Neurochem 94:1473–1487. https://doi.org/10.1111/j.1471-4159.2005.03315.x
Kobayashi M, Masaki T, Hori K, Masuo Y, Miyamoto M, Tsubokawa H, Noguchi H, Nomura M, Takamatsu K (2005) Hippocalcin-deficient mice display a defect in cAMP response element-binding protein activation associated with impaired spatial and associative memory. Neuroscience 133:471–484. https://doi.org/10.1016/j.neuroscience.2005.02.034
Kopach O, Viatchenko-Karpinski V, Atianjoh FE, Belan P, Tao YX, Voitenko N (2013) PKCalpha is required for inflammation-induced trafficking of extrasynaptic AMPA receptors in tonically firing lamina II dorsal horn neurons during the maintenance of persistent inflammatory pain. J Pain 14:182–192. https://doi.org/10.1016/j.jpain.2012.10.015
Lee M, Jo Y, Chun M, Chung J, Kim M, Min D (2000) Immunohistochemical localization of phospholipase D1 in rat central nervous system. Brain Res 864:52–59
Lee SI, Kim BG, Hwang DH, Kim HM, Kim SU (2009) Overexpression of Bcl-XL in human neural stem cells promotes graft survival and functional recovery following transplantation in spinal cord injury. J Neurosci Res 87:3186–3197. https://doi.org/10.1002/jnr.22149
Liu W, Yue W, Wu R (2013) Overexpression of Bcl-2 promotes survival and differentiation of neuroepithelial stem cells after transplantation into rat aganglionic colon. Stem Cell Res Ther 4:7. https://doi.org/10.1186/scrt155
Lundgren TK, Nakahata K, Fritz N, Rebellato P, Zhang S, Uhlen P (2012) RET PLCgamma phosphotyrosine binding domain regulates Ca2+ signaling and neocortical neuronal migration. PLoS One 7:e31258. https://doi.org/10.1371/journal.pone.0031258
Luo LD, Li G, Wang Y (2017) PLD1 promotes dendritic spine development by inhibiting ADAM10-mediated N-cadherin cleavage. Sci Rep 7:6035. https://doi.org/10.1038/s41598-017-06121-2
Masuo Y, Ogura A, Kobayashi M, Masaki T, Furuta Y, Ono T, Takamatsu K (2007) Hippocalcin protects hippocampal neurons against excitotoxin damage by enhancing calcium extrusion. Neuroscience 145:495–504. https://doi.org/10.1016/j.neuroscience.2006.12.011
Miller FD, Gauthier AS (2007) Timing is everything: making neurons versus glia in the developing cortex. Neuron 54:357–369. https://doi.org/10.1016/j.neuron.2007.04.019
Min DS, Ahn BH, Rhie DJ, Yoon SH, Hahn SJ, Kim MS, Jo YH (2001) Expression and regulation of phospholipase D during neuronal differentiation of PC12 cells. Neuropharmacology 41:384–391
Morrison SJ (2001) Neuronal differentiation: proneural genes inhibit gliogenesis. Curr Biol 11:R349–R351
Mudo G, Bonomo A, Di Liberto V, Frinchi M, Fuxe K, Belluardo N (2009) The FGF-2/FGFRs neurotrophic system promotes neurogenesis in the adult brain. J Neural Transm 116:995–1005. https://doi.org/10.1007/s00702-009-0207-z
Nakashima K, Yanagisawa M, Arakawa H, Kimura N, Hisatsune T, Kawabata M, Miyazono K, Taga T (1999) Synergistic signaling in fetal brain by STAT3-Smad1 complex bridged by p300. Science 284:479–482
Oh DY, Cho JH, Park SY, Kim YS, Yoon YJ, Yoon SH, Chung KC, Lee KS, Han JS (2008) A novel role of hippocalcin in bFGF-induced neurite outgrowth of H19-7 cells. J Neurosci Res 86:1557–1565. https://doi.org/10.1002/jnr.21602
Park SY, Cho JH, Oh DY, Park JW, Ahn MJ, Han JS, Oh JW (2009) House dust mite allergen Der f 2-induced phospholipase D1 activation is critical for the production of interleukin-13 through activating transcription factor-2 activation in human bronchial epithelial cells. J Biol Chem 284:20099–20110. https://doi.org/10.1074/jbc.M109.010017
Park SY, Ma W, Yoon SN, Kang MJ, Han JS (2015) Phospholipase D1 increases Bcl-2 expression during neuronal differentiation of rat neural stem cells. Mol Neurobiol 51:1089–1102. https://doi.org/10.1007/s12035-014-8773-y
Park SY, Yoon SN, Kang MJ, Lee Y, Jung SJ, Han JS (2017) Hippocalcin promotes neuronal differentiation and inhibits astrocytic differentiation in neural stem cells. Stem Cell Rep 8:95–111. https://doi.org/10.1016/j.stemcr.2016.11.009
Paspala SA, Murthy TV, Mahaboob VS, Habeeb MA (2011) Pluripotent stem cells—a review of the current status in neural regeneration. Neurol India 59:558–565. https://doi.org/10.4103/0028-3886.84338
Powner DJ, Wakelam MJ (2002) The regulation of phospholipase D by inositol phospholipids and small GTPases. FEBS Lett 531:62–64
Rash BG, Lim HD, Breunig JJ, Vaccarino FM (2011) FGF signaling expands embryonic cortical surface area by regulating Notch-dependent neurogenesis. J Neurosci 31:15604–15617. https://doi.org/10.1523/JNEUROSCI.4439-11.2011
Reynolds BA, Weiss S (1992) Generation of neurons and astrocytes from isolated cells of the adult mammalian central nervous system. Science 255:1707–1710
Rudge SA, Wakelam MJ (2009) Inter-regulatory dynamics of phospholipase D and the actin cytoskeleton. Biochim Biophys Acta 1791:856–861. https://doi.org/10.1016/j.bbalip.2009.04.008
Saitoh S, Takamatsu K, Kobayashi M, Noguchi T (1994) Expression of hippocalcin in the developing rat brain research. Dev Brain Res 80:199–208
Sun Y, Nadal-Vicens M, Misono S, Lin MZ, Zubiaga A, Hua X, Fan G, Greenberg ME (2001) Neurogenin promotes neurogenesis and inhibits glial differentiation by independent mechanisms. Cell 104:365–376
Sung JY, Lee SY, Min DS, Eom TY, Ahn YS, Choi MU, Kwon YK, Chung KC (2001) Differential activation of phospholipases by mitogenic EGF and neurogenic PDGF in immortalized hippocampal stem cell lines. J Neurochem 78:1044–1053
Sung TC, Roper RL, Zhang Y, Rudge SA, Temel R, Hammond SM, Morris AJ, Moss B, Engebrecht J, Frohman MA (1997) Mutagenesis of phospholipase D defines a superfamily including a trans-Golgi viral protein required for poxvirus pathogenicity. EMBO J 16:4519–4530. https://doi.org/10.1093/emboj/16.15.4519
Sung TC, Zhang Y, Morris AJ, Frohman MA (1999) Structural analysis of human phospholipase D1. J Biol Chem 274:3659–3666
Threadgill R, Bobb K, Ghosh A (1997) Regulation of dendritic growth and remodeling by Rho, Rac, and Cdc42. Neuron 19:625–634
Toth AB, Shum AK, Prakriya M (2016) Regulation of neurogenesis by calcium signaling. Cell Calcium 59:124–134. https://doi.org/10.1016/j.ceca.2016.02.011
Trouillas M, Saucourt C, Duval D, Gauthereau X, Thibault C, Dembele D, Feraud O, Menager J, Rallu M, Pradier L, Boeuf H (2008) Bcl2, a transcriptional target of p38alpha, is critical for neuronal commitment of mouse embryonic stem cells. Cell Death Differ 15:1450–1459. https://doi.org/10.1038/cdd.2008.63
Urban N, Guillemot F (2014) Neurogenesis in the embryonic and adult brain: same regulators, different roles. Front Cell Neurosci 8:396. https://doi.org/10.3389/fncel.2014.00396
Vescovi AL, Reynolds BA, Fraser DD, Weiss S (1993) bFGF regulates the proliferative fate of unipotent (neuronal) and bipotent (neuronal/astroglial) EGF-generated CNS progenitor cells. Neuron 11:951–966
Watanabe H, Yokozeki T, Yamazaki M, Miyazaki H, Sasaki T, Maehama T, Itoh K, Frohman MA, Kanaho Y (2004) Essential role for phospholipase D2 activation downstream of ERK MAP kinase in nerve growth factor-stimulated neurite outgrowth from PC12 cells. J Biol Chem 279:37870–37877. https://doi.org/10.1074/jbc.M402610200
Xu W, Lakshman N, Morshead CM (2017) Building a central nervous system: the neural stem cell lineage revealed. Neurogenesis 4:e1300037. https://doi.org/10.1080/23262133.2017.1300037
Xu Y, Seet LF, Hanson B, Hong W (2001) The Phox homology (PX) domain, a new player in phosphoinositide signalling. The Biochemical Journal 360:513–530
Yokogami K, Wakisaka S, Avruch J, Reeves SA (2000) Serine phosphorylation and maximal activation of STAT3 during CNTF signaling is mediated by the rapamycin target mTOR. Curr Biol 10:47–50
Yoon MS, Cho CH, Lee KS, Han JS (2006) Binding of Cdc42 to phospholipase D1 is important in neurite outgrowth of neural stem cells. Biochem Biophys Res Commun 347:594–600. https://doi.org/10.1016/j.bbrc.2006.06.111
Yoon MS, Yon C, Park SY, Oh DY, Han AH, Kim DS, Han JS (2005) Role of phospholipase D1 in neurite outgrowth of neural stem cells. Biochem Biophys Res Commun 329:804–811. https://doi.org/10.1016/j.bbrc.2005.02.087
Yoon SN, Kim KS, Cho JH, Ma W, Choi HJ, Kwon SJ, Han JS (2012) Phospholipase D1 mediates bFGF-induced Bcl-2 expression leading to neurite outgrowth in H19-7 cells. Biochem J 441:407–416. https://doi.org/10.1042/BJ20110302
Yun DH, Jeon ES, Sung SM, Ryu SH, Kim JH (2006) Lysophosphatidylcholine suppresses apoptosis and induces neurite outgrowth in PC12 cells through activation of phospholipase D2. Exp Mol Med 38:375–384. https://doi.org/10.1038/emm.2006.44
Zhao C, Du G, Skowronek K, Frohman MA, Bar-Sagi D (2007) Phospholipase D2-generated phosphatidic acid couples EGFR stimulation to Ras activation by Sos. Nat Cell Biol 9:706–712. https://doi.org/10.1038/ncb1594
Zheng JQ, Poo MM (2007) Calcium signaling in neuronal motility. Annu Rev Cell Dev Biol 23:375–404. https://doi.org/10.1146/annurev.cellbio.23.090506.123221
Zhu YB, Kang K, Zhang Y, Qi C, Li G, Yin DM, Wang Y (2012) PLD1 negatively regulates dendritic branching. J Neurosci 32:7960–7969. https://doi.org/10.1523/JNEUROSCI.5378-11.2012
Acknowledgements
This work was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF), funded by the Ministry of Science, ICT, & Future Planning (NRF-2015R1C1A1A02037376), and partly supported by the Korea government (MSIP) (NRF-2016R1A2B4015358).
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of Interest
The authors declare that they have no conflict of interest.
Rights and permissions
Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.
About this article
Cite this article
Park, SY., Han, JS. Phospholipase D1 Signaling: Essential Roles in Neural Stem Cell Differentiation. J Mol Neurosci 64, 333–340 (2018). https://doi.org/10.1007/s12031-018-1042-1
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12031-018-1042-1