Pten: Biological Overview | Evolutionary Homologs | Regulation | Developmental Biology | Effects of Mutation | References

Gene name - Pten

Synonyms -

Cytological map position - 31B--31C

Function - signaling protein

Keywords - growth response, insulin signaling pathway, cytoskeleton, tumor suppressor

Symbol - Pten

FlyBase ID: FBgn0026379

Genetic map position -

Classification - protein tyrosine phosphatase

Cellular location - cytoplasmic



NCBI links: HomoloGene | Entrez Gene | UniGene

Recent literature
Marmor-Kollet, N. and Schuldiner, O. (2015). Contrasting developmental axon regrowth and neurite sprouting of Drosophila mushroom body neurons reveals shared and unique molecular mechanisms. Dev Neurobiol. PubMed ID: 26037037
Summary:
The molecular mechanisms regulating intrinsic axon growth potential during development or following injury remain largely unknown despite their vast importance. This study has established a neurite sprouting assay of primary cultured mushroom body (MB) neurons. This study used the MARCM technique to both mark and manipulate MB neurons, enabling quantification of the sprouting abilities of single WT and mutant neurons originating from flies at different developmental stages. Sprouting of dissociated MB neurons was dependent on wnd, the DLK ortholog, a conserved gene that is required for axon regeneration. Next, and as expected, the sprouting ability of adult MB neurons was found to be significantly decreased. In contrast, and surprisingly, it was found that pupal-derived neurons exhibit increased sprouting compared with neurons derived from larvae, suggesting the existence of an elevated growth potential state. The molecular requirements of neurite sprouting was then contrasted to developmental axon regrowth of MB neurons, a process that requires the nuclear receptor UNF acting via the target of rapamycin (TOR) pathway. Strikingly, it was found that while TOR was required for neurite sprouting, UNF was not. In contrast, PTEN was found to inhibit sprouting in adult neurons, suggesting that TOR is regulated by the PI3K/PTEN pathway during sprouting and by UNF during developmental regrowth. Interestingly, the PI3K pathway as well as Wnd were not required for developmental regrowth nor for initial axon outgrowth suggesting that axon growth during circuit formation, remodeling, and regeneration share some molecular components but differ in others.

Zhang, L., et al. (2015). Microenvironment-induced PTEN loss by exosomal microRNA primes brain metastasis outgrowth. Nature 527: 100-104. PubMed ID: 26479035
Summary:
The development of life-threatening cancer metastases at distant organs requires disseminated tumour cells' adaptation to, and co-evolution with, the drastically different microenvironments of metastatic sites. Cancer cells of common origin manifest distinct gene expression patterns after metastasizing to different organs. It is unclear when and how disseminated tumour cells acquire the essential traits from the microenvironment of metastatic organs that prime their subsequent outgrowth. This study shows that both human and mouse tumour cells with normal expression of PTEN, an important tumour suppressor, lose PTEN expression after dissemination to the brain, but not to other organs. The PTEN level in PTEN-loss brain metastatic tumour cells is restored after leaving the brain microenvironment. This brain microenvironment-dependent, reversible PTEN messenger RNA and protein downregulation is epigenetically regulated by microRNAs from brain astrocytes. Mechanistically, astrocyte-derived exosomes mediate an intercellular transfer of PTEN-targeting microRNAs to metastatic tumour cells, while astrocyte-specific depletion of PTEN-targeting microRNAs or blockade of astrocyte exosome secretion rescues the PTEN loss and suppresses brain metastasis in vivo. These findings demonstrate a remarkable plasticity of PTEN expression in metastatic tumour cells in response to different organ microenvironments, underpinning an essential role of co-evolution between the metastatic cells and their microenvironment during the adaptive metastatic outgrowth.

Mensah, L. B., Davison, C., Fan, S. J., Morris, J. F., Goberdhan, D. C. and Wilson, C. (2015). Fine-Tuning of PI3K/AKT signalling by the tumour suppressor PTEN is required for maintenance of flight muscle function and mitochondrial integrity in ageing adult Drosophila melanogaster. PLoS One 10: e0143818. PubMed ID: 26599788
Summary:
Insulin/insulin-like growth factor signalling (IIS), acting primarily through the PI3-kinase (PI3K)/AKT kinase signalling cassette, plays key evolutionarily conserved regulatory roles in nutrient homeostasis, growth, ageing and longevity. This study identified a novel hypomorphic allele of PI3K's direct antagonist, Pten, in Drosophila. Adults carrying combinations of this allele, Pten5, combined with strong loss-of-function Pten mutations exhibit subtle or no increase in mass, but are highly susceptible to a wide range of stresses. They also exhibit dramatic upregulation of the oxidative stress response gene, GstD1, and a progressive loss of motor function that ultimately leads to defects in climbing and flight ability. The latter phenotype is associated with mitochondrial disruption in indirect flight muscles, although overall muscle structure appears to be maintained. The phenotype is partially rescued by muscle-specific expression of the Bcl-2 homologue Buffy, which in flies, maintains mitochondrial integrity, modulates energy homeostasis and suppresses cell death. The flightless phenotype is also suppressed by mutations in downstream IIS signalling components, including those in the mechanistic Target of Rapamycin Complex 1 (mTORC1) pathway, suggesting that elevated IIS is responsible for functional decline in flight muscle. These data demonstrate that IIS levels must be precisely regulated by Pten in adults to maintain the function of the highly metabolically active indirect flight muscles, offering a new system to study the in vivo roles of IIS in the maintenance of mitochondrial integrity and adult ageing.
Mensah, L. B., Goberdhan, D. C. and Wilson, C. (2017). mTORC1 signalling mediates PI3K-dependent large lipid droplet accumulation in Drosophila ovarian nurse cells. Biol Open [Epub ahead of print]. PubMed ID: 28302666
Summary:
Insulin and insulin-like growth factor signalling (IIS), which is primarily mediated by the PI3-kinase (PI3K)/PTEN/Akt kinase signalling cassette, is a highly evolutionary conserved pathway involved in co-ordinating growth, development, ageing and nutrient homeostasis with dietary intake. It controls transcriptional regulators, in addition to promoting signalling by mechanistic Target of Rapamycin (mTOR) Complex 1 (mTORC1; see Tor), which stimulates biosynthesis of proteins and other macromolecules, and drives organismal growth. Previous studies in nutrient-storing germline nurse cells of the Drosophila ovary showed that a cytoplasmic pool of activated phosphorylated Akt (pAkt) controlled by Pten, an antagonist of IIS, cell-autonomously regulates accumulation of large lipid droplets in these cells at late stages of oogenesis. This study shows that the large lipid droplet phenotype induced by Pten mutation is strongly suppressed when mTor function is removed. Furthermore, nurse cells lacking either Tsc1 or Tsc2, which negatively regulate mTORC1 activity, also accumulate large lipid droplets via a mechanism involving Rheb, the downstream G-protein target of TSC2, which positively regulates mTORC1. It is concluded that elevated IIS/mTORC1 signalling is both necessary and sufficient to induce large lipid droplet formation in late-stage nurse cells, suggesting roles for this pathway in aspects of lipid droplet biogenesis, in addition to control of lipid metabolism.
BIOLOGICAL OVERVIEW

The human tumor suppressor gene PTEN gets its name from its biochemical function, its domain structure and its chromosomal location: PTEN stands for the combination of phosphatase and tensin homolog on chromosome 10 (J. Li, 1997). The protein is also known as MMAC1 (Steck, 1997) or TEP1 (D. Li, 1997). The protein exhibits phosphatase activity against proteins and lipid phosphate residues. The PTEN protein contains a protein phosphatase domain with similarity to dual specificity phosphatases (D. Li, 1997; Li and Sun, 1997; Steck, 1997). Dual specificity phosphatases act both on serine/threonine and tyrosine phosphotyrosine residues. The phosphatase domain is embedded within a domain with homology to an actin-binding motif in the focal adhesion-associated protein tensin. Immunohistochemical evidence has suggested that like tensin, PTEN is associated with the cytoskeleton (D. Li, 1997).

Now that the domain structure of PTEN has been described, the known and potential functions of the PTEN homolog in Drosophila and mammals is presented. The lipid phosphatase function of PTEN places it in the middle of the insulin pathway, known to involve lipid signaling (Goberdhan, 1999; Huang, 1999). Drosophila Pten modulates cell size, and consequently tissue mass, by acting antagonistically to the lipid modifiying enzyme Phosphotidylinositol 3 kinase 92E, also known as Dp110, and its upstream activator Chico, an insulin receptor binding and signal transduction protein (Goberdhan, 1999). All signals from the Insulin-like receptor can be antagonized by Pten (Huang, 1999). In terms of its protein phosphatase function, mammalian PTEN targets focal adhesion kinase, a major effector of cytoskeletal function. Overexpression of wild-type mammalian PTEN and mutant PTEN that lacks lipid phosphatase activity can reduce levels of focal adhesion kinase (FAK: see Drosophila Focal adhesion kinase-like) phosphorylation and the formation of focal adhesions, thereby inhibiting cell migration and invasiveness (Tamura, 1998). In terms of its cytoskeletal connection, Drosophila Pten appears to regulate the subcellular organization of the actin cytoskeleton in multiple cell types. The bristle, hair, and rhabdomere phenotypes observed in Drosophila Pten mutant tissue have not been reported in flies defective in insulin or Dp110 signaling, indicating that unlike the Pten-linked growth defects, involving insulin signaling, these effects are probably not derived from alterations in lipid signaling but from direct influences on cytoskeletal function (Goberdhan, 1999).

The tumor suppressor gene PTEN is one of the most frequently mutated genes involved in the development of mammalian cancer. PTEN mutations are found in a wide variety of tumors such as glioblastomas, endometrial carcinomas, advanced prostate cancers and melanoma cells. Germ-line mutations in PTEN are linked to three rare autosomal dominant syndromes: Cowden Disease, Bannayan-Zonana syndrome and Lhermitte-Duclose disease. A common feature of these syndromes is a predisposition for the development of hamartomas: benign tumors that have differentiated but disorganized cells. Pten mutant mice exhibit early embryonic lethality (E7.5-E9.5) and the heterozygotes display a predisposition to tumor development. Consistent with the role for PTEN as a lipid phosphatase, Pten mutant cells exhibit increased lipid signaling. The C. elegans gene daf-18 encodes a distant PTEN homolog. In addition to a conserved phosphatase domain, daf-18 encodes a large non-homologous C-terminal region. Daf-18 is associated with the insulin signaling pathway. In C. elegans, daf-18 mutants can suppress the mutant phenotypes of daf-2, the C. elegans insulin-like receptor, and age-1, the C. elegans PI3K homolog (Huang, 1999 and references therein).

Drosophila Pten was identified in two laboratories using two different approaches, one based on homology to mammalian PTEN (Huang, 1999) and the second based on intensive analysis of a chromosomal region containing several other genes coding for signaling proteins (Goberdhan, 1999). This second approach will be examined in detail, since it foreshadows future approaches that will be taken to analyze Drosophila genes based on genomics. Previously, two Drosophila genes had been identified in the vicinity of the gene that was later to be identified as Drosophila Pten: Dror encodes a neural-specific receptor tyrosine kinase, and basket encodes the homolog of c-Jun amino-terminal kinase. These two genes map adjacent to each other at 31B/C on the second chromosome. Several deficiency chromosomes have been characterized that uncover one or both of these genes and also affect the adjacent gene chico , which codes for a homolog of mammalian insulin receptor substrates, IRS1-4 (Böhni, 1999). One of these deficiencies, Df(2L)170B, is of particular interest because it deletes sequences proximal to Dror and produces an overgrowth phenotype in homozygous clones. This effect was not observed with deficiencies [Df(2L)41C and Df(2L)147F] that only delete Dror, DJNK, and chico. Clones generated with these smaller deficiencies contain reduced numbers of small cells attributable to the loss of chico function (Böhni, 1999). During a chemical mutagenesis screen using the Df(2L)170B chromosome, a new lethal complementation group has been identified that maps proximal to Dror and affects tissue growth. Sequence analysis of genomic and cDNA clones reveals a novel gene at this locus encoding the Drosophila PTEN homolog, Pten (Goberdhan, 1999).

Drosophila Pten regulates cell number and size and affects assembly of specific cytoskeleton-dependent structures. Because animals transheterozygous for strong Pten alleles die with no obvious phenotypes, the functions of this gene have been elucidated further by generating homozygous mutant clones in heterozygous animals using the FLP/FRT system. Two Pten alleles, DPTEN1 and DPTEN3, produce growth phenotypes slightly more severe than those generated by Df(2L)170B, the chromosomal deficiency deleting Pten, Dror, DJNK, and chico. DPTEN1 and DPTEN3 also behave in a manner similar to the deficiency in combination with a weak, nonlethal Pten mutation; this suggests that they are strong or null Pten alleles (Goberdhan, 1999).

The adult compound eye in Drosophila is composed of ~700 regularly arranged unit eyes or ommatidia, each containing the same complement of photoreceptors and accessory cells. Mutant clones can be generated in the eye and other tissues by somatic recombination of homologous chromosomes in heterozygous animals. If only the nonmutant chromosome and not the mutant chromosome is marked with a copy of the white (w+) gene, mutant clones can be distinguished by the absence of pigment. The wild-type twin spot resulting from a recombination event with these chromosomes contains increased levels of pigment relative to the remainder of the eye, because the cells in this region carry two copies of the w+ gene. Ommatidia within clones homozygous for DPTEN1, DPTEN3, or Df(2L)170B are enlarged and bulge from the surface of the eye. Ommatidial facets are occasionally fused, and there frequently are clusters of morphologically abnormal interommatidial bristles or clustered sockets in mutant regions, particularly (but not exclusively) in the dorsal half of the eye. To assess the effect of loss of Pten function on the regulation of cell number, the numbers of ommatidia in multiple mutant clones and their wild-type twin spots were compared. Mutant clones typically contain at least twice as many ommatidia as neighboring twin spots, suggesting that mutant cells overproliferate, a result supported by analysis of clones at larval stages. The largest Pten clones include more than half of the adult eye and form a hyperplastic tumor-like overgrowth. This hyperplastic phenotype, however, is mild compared to the effects of several other tumor suppressor mutations in Drosophila (Goberdhan, 1999).

Sections demonstrate that the number and identities of ommatidial cells are not obviously altered in Pten mutant clones, indicating that this gene does not have a major role in specifying cell fate in the eye. Analysis of nonpigmented mutant clones, however, reveals that the cell bodies of all mutant photoreceptors are greatly enlarged, but not those of their wild-type/heterozygous neighbors. By using a w+-marked mutant chromosome to visualize the pigment cell layer in clones, it is possible to show that the volume of this layer is also increased. These cellular growth defects account for the increased size of mutant ommatidia. Furthermore, in mutant photoreceptors, the light-sensing rhabdomeres are elliptical and not circular in cross-section. This phenotype is observed in several mutants that are believed to affect assembly of the actin cytoskeleton. Analysis of ommatidia that contain both wild-type and mutant photoreceptors reveals that both the cell size and rhabdomeric phenotypes are cell-autonomous (Goberdhan, 1999).

Cells in the wing, each of which normally possesses a single wing hair, are also significantly enlarged in mutant Pten clones. Wing hairs are occasionally duplicated, a defect observed under conditions where the cytoskeleton of wing epithelial cells is disrupted. In addition, crossvein formation in the wing, a process involving specialized contacts between wing epithelial cells and the extracellular matrix (ECM), is abnormal in mutant regions. In ~70% of cases, anterior cross-veins are absent or partially absent in mutant clones, whereas the posterior cross-vein is affected in ~35% of cases. Occasionally, extra wing vein material is observed. Longitudinal veins are affected only very rarely (Goberdhan, 1999).

Overexpression of Pten also produces enlargement of wing cells. Wild-type Pten cDNA is overexpressed in particular areas of the wing using the GAL4-UAS system. Initially flies carrying a dpp-GAL4 construct were used. This drives gene expression in cells that will normally populate the region between the third and fourth longitudinal wing veins (LIII and LIV). Overexpression of Pten reduces the size of these regions by nearly 25% compared with wild type. This is not a consequence of a general reduction in wing size in overexpressing flies, since an adjacent area of the wing between LIV and LV is essentially unaffected. The effect on wing area is similar to that produced by overexpression of Dp110D954A, a dominant-negative, kinase-dead version of Pi3K92E. The reduction is caused by both a decrease in cell size and cell number and is opposite of the effect of overexpressing an activated, membrane-associated form of Pi3K92E, Dp110-CAAX, in the same region. To test whether Pten's growth regulatory functions are primarily mediated by its effects on the insulin receptor-Pi3K92E signaling pathway and not by an independent signaling cascade, the genetic effects of Pten alleles were sought using mutant phenotypes associated with chico and Pi3K92E (Goberdhan, 1999).

Interestingly, both overexpression of a dominant negative form of Phosphotidylinositol 3 kinase 92E (also known as Dp110 or Pi3K92E) and mutations either in the Drosophila insulin receptor or in chico/IRS1-4 also reduce cell size as well as proliferation. Furthermore, overexpression of wild-type and activated forms of Pi3K92E produces similar size and proliferation defects as those seen in Pten mutant cells. These observations are consistent with a model in which growth is regulated in Drosophila by specific phosphoinositides whose levels are controlled by the balance of Pten and Pi3K92E activities. Pten and Pi3K92E. At 25°C, flies do not survive to adult when wild-type Pi3K92E is ectopically expressed by means eyeless-GAL4. Interestingly, this lethality can be rescued by coexpression of Pten. Furthermore, the small eye phenotype of Pten overexpression is suppressed by overexpression of wild-type Pi3K92E and enhanced by overexpression of dominant negative Pi3K92E. These results clearly indicate that Pten and Pi3K92E function antagonistically in Drosophila. The recent characterization of chico, a Drosophila IRS1-4 homolog, has shown that chico, Pi3K92E and Insulin receptor(Inr) act as positive elements in a Drosophila insulin signaling pathway to regulate cell proliferation and cell size (Bohni, 1999). Consistent with the role of Pten as a negative regulator in this insulin pathway, removal of one copy of the chico gene genetically enhances the eye/Pten eye phenotype. Overexpression of Inr (eye/Inr) causes lethality at 25°C. At room temperature, few animals survive with overproliferated eyes. Strikingly, co-overexpression of Pten completely rescues lethality and the overproliferation phenotype. This suggests that all signals from the insulin receptor can be antagonized by Pten function. Together with the previous findings that mammalian and C. elegans PTEN molecules interact with components of the insulin pathway (Furnari, 1998; Maehama, 1998; Myers, 1998; Ogg , 1998; Stambolic, 1998; Sun, 1999), these genetic data argue that PTEN functions as a major conserved negative regulator in the insulin signaling pathway (Huang, 1999).

The importance of Drosophila Pten in negatively regulating the growth-promoting effects of insulin signaling in vivo, however, is best illustrated in homozygous clones mutant for both chico and Pten. In these clones, the reduced growth phenotype normally seen in chico mutant cells is masked completely by the overgrowth phenotype associated with loss of Pten function, suggesting that Pten normally has a critical role downstream of Chico in maintaining growth-promoting signals at nonhyperplastic levels (Goberdhan, 1999).

Pten also affects the organization of the actin cytoskeleton in differentiating adult cells. The bristle, hair, and rhabdomere phenotypes observed in Pten mutant tissue have not been reported in flies defective in insulin or Dp110 signaling, indicating that unlike the Pten-linked growth defects, these effects are probably not caused simply by an increase in PIP3 levels. Pten mutant clones have been analyzed in the larval imaginal discs to determine whether there is an underlying defect in microfilament organization during differentiation that might explain these phenotypes. Consistent with the adult eye phenotype, Pten mutant ommatidial preclusters in the eye imaginal disc were more widely spaced, and specific staining of photoreceptors indicates that these cells are enlarged in mutant clones. Phalloidin staining demonstrates that there are defects in the actin cytoskeletal network in mutant tissue. In particular, analysis of mutant photoreceptors reveals disorganization in the most basal part of the apical cytoskeleton, the scaffold on which apical photoreceptor projections are normally assembled in the disc. An altered distribution of neighboring actin microfilaments is also observed. Because rhabdomere assembly in photoreceptors requires the apical cytoskeleton, this defect may account for the rhabdomeric phenotype seen in adult Pten mutant ommatidia. Analysis of the wing imaginal disc also shows disturbed cytoskeletal organization in mutant tissue. Therefore, although Pten mutant cells can still assemble actin microfilaments, the subcellular regulation of this process appears to be abnormal, potentially accounting for the structural defects in adult bristles, rhabdomeres, and wing hairs. One interesting hypothesis that remains to be tested is that these effects on the cytoskeleton may have an important role in regulating cell growth by controlling spreading and shape change at the cell surface. It is intriguing to speculate that the loss of Pten function might alter communication between the peripheral actin cytoskeleton, the plasma membrane and the extracellular matrix, and therefore affect the invasiveness of cells (Goberdhan, 1999), as has been suggested from studies in mammalian cell culture (Tamura, 1998).

Regeneration of Drosophila sensory neuron axons and dendrites is regulated by the Akt pathway involving Pten and microRNA bantam

Both cell-intrinsic and extrinsic pathways govern axon regeneration, but only a limited number of factors have been identified and it is not clear to what extent axon regeneration is evolutionarily conserved. Whether dendrites also regenerate is unknown. This study reports that, like the axons of mammalian sensory neurons, the axons of certain Drosophila dendritic arborization (da) neurons are capable of substantial regeneration in the periphery but not in the CNS, and activating the Akt pathway enhances axon regeneration in the CNS. Moreover, those da neurons capable of axon regeneration also display dendrite regeneration, which is cell type-specific, developmentally regulated, and associated with microtubule polarity reversal. Dendrite regeneration is restrained via inhibition of the Akt pathway in da neurons by the epithelial cell-derived microRNA bantam but is facilitated by cell-autonomous activation of the Akt pathway. This study begins to reveal mechanisms for dendrite regeneration, which depends on both extrinsic and intrinsic factors, including the PTEN-Akt pathway that is also important for axon regeneration. This study has thus established an important new model system -- the fly da neuron regeneration model that resembles the mammalian injury model -- with which to study and gain novel insights into the regeneration machinery (Song, 2012).

The present study shows that Drosophila sensory neuron dendrites and axons are capable of regeneration in a cell type-specific manner. While dendrites and axons share the same cell type specificity in their capacity for regeneration, they differ in their developmental regulation, with axons but not dendrites retaining the regeneration ability throughout larval development. It was further shown that the evolutionarily conserved PTEN-Akt signaling pathway is important for the regeneration of dendrites as well as axons and that both axon regeneration and dendrite regeneration are accompanied by the reversal of microtubule polarity (Song, 2012).

It is known that Drosophila larval axons undergo a scaling process in which axons substantially increase their length in accordance with the growth of the organism. Thus, it raises an important issue of whether larval axons regenerate or simply scale after axotomy. This question may be addressed with the following two considerations. First, larval axons scale while maintaining their neural connections; da neuron axons have already formed synaptic connections with neurons in the VNC, and these axon projections are not significantly altered as larvae grow in size. Therefore, this increase of axon length does not involve bona fide axon pathfinding or synaptogenesis. Thus, axon scaling differs from the developmental axon outgrowth before synapse formation and is different from axon regeneration, which involves reinitiation of the developmental program for severed axons to generate growth cones or growth cone-like structures and pathfind to reach their targets. In the larval injury model, the axon is severed and therefore develops a new growing tip, reroutes following the presumptive trajectory by active or passive cues, and may or may not eventually establish synaptic contacts with their right targets in the CNS. This process resembles the regeneration program rather than axon scaling. Second, all of the da neurons, including class I, class III, and class IV, show similar axon scaling during larval stages. However, class IV but not class I or class III da neurons displayed axon regrowth after axotomy. The fact that only class IV da neurons are capable of regrowth, although all of these different types of da neurons undergo scaling, strongly suggests that class IV da neurons possess a unique regrowth potential that allows their severed axons to reinitiate the developmental program for axon outgrowth. For these reasons, it is believed that a subset of the larval axons can regenerate after injury, although the possibility cannot be excluded that the ability of these axons to scale contributes to their regeneration potential. While this regeneration process may or may not fully recapitulate the regeneration program in adults, understanding how this process takes place in larvae will provide invaluable insights into the axon regeneration machinery (Song, 2012).

The ability of class IV but not class I or class III da neurons to readily regenerate their axons and dendrites could conceivably reflect cell type-specific features, including the transcription programs. One interesting question is whether the same program that governs the cell type morphology may also influence their regeneration capacity. For dendrite regeneration of class IV da neurons, either the regenerated dendrite or the neighboring dendritic branch continues to grow to fill the available space. Thus, they may possess a persistent growing potential that is inhibited by neighboring branches nearby so that the branches might overgrow if those inhibitory signals are removed. Therefore, with some branches removed due to injury, the remaining branches will regrow to take over the vacant space. Since class I and class III da neuron dendrites show very limited space-filling ability, these dendrites may lack the growth potential required for regeneration (Song, 2012).

In response to injury, class IV da neurons regenerate their axons substantially, while class I da neurons partially reverse the microtubule polarity of nearby dendrites and convert one of these dendrites into a pseudo-axon (Stone, 2010). Taken together with the current finding that class IV but not class I or class III da neurons are able to regenerate their dendrites, which are also associated with the reversal of microtubule polarity, these observations raise the question of whether pathways controlling neuronal polarity and/or cytoskeletal rearrangement may influence dendrite and axon regeneration (Song, 2012).

Several lines of evidence suggest that dendrite regeneration depends on a balance of influences. First, there may be competition between de novo dendrite regeneration and invasion of neighboring branches. Successful regeneration prevents invasion and vice versa. Second, there could be a balance of extrinsic inhibitory cues, as in the form of the ban miRNA in epithelial cells, and intrinsic growth-promoting signals, as conveyed by the activation of the Akt pathway (Song, 2012).

Moreover, given that activation of the Akt pathway at later stages of development is not sufficient to elevate the extent of dendrite regeneration to that during early larval development, it seems likely that either factors downstream from Akt are developmentally regulated to turn off the regeneration program at later stages or, alternatively, other pathways may contribute to this inhibition (Song, 2012).

Whereas dendrite and axon regeneration display differences with respect to developmental regulation, the PTEN-Akt pathway is important for regeneration of axons as well as dendrites. This pathway not only regulates the extent of dendrite growth of class IV da neurons during development, but also affects their dendrite regeneration and axon regeneration in the CNS. Together with previous work (Park, 2008; Liu, 2010), these results support the notion that modulating neuronal intrinsic PTEN and Akt activity is a potential therapeutic strategy for promoting axon regeneration and functional repair after CNS trauma (Song, 2012).

This work focuses on class IV da neurons, which behave very differently from class I da neurons in regeneration. In particular, unlike class I da neurons, the class IV da neuron is capable of regenerating its axon in the periphery but not inside the CNS, thereby providing the first example of this phenomenon in invertebrates. A recent study of Caenorhabditis elegans PLM neurons, a type of mechanosensory neurons that consistently regrow their axons upon laser-mediated axotomy, has identified multiple genes important for axon regeneration (Chen, 2011), illustrating the power of the genetic approach. The injury model involving Drosophila class IV da neuron axotomy in the CNS (VNC) in the current study has the additional feature that it resembles the injury model involving mammalian DRG neuron axotomy in the CNS (spinal cord) at the cellular and molecular level: Both da neuron and DRG neuron axons regenerate poorly in the CNS even though they display robust regeneration in the periphery, and in both cases, axon regeneration in the CNS is enhanced by activation of the PTEN-Akt pathway. Importantly, while the PTEN-Akt pathway has been shown to be critical for mammalian axon regeneration in the CNS, this has not been shown in invertebrate models; for example, in C. elegans, PTEN (DAF-18) has no effect on axon regrowth. The current finding underscores the usefulness of the Drosophila system that this study developed as a model to uncover evolutionarily conserved mechanisms for CNS axon regeneration. Moreover, the elaborate and stereotyped dendritic branching pattern of da neurons provides a sensitive assay system to begin studying the injury responses and regeneration of dendrites, which may yield clues to facilitate studies of mammalian neuronal dendrites and identify novel approaches to promote dendrite recovery for the treatment of nervous system trauma (Song, 2012).


GENE STRUCTURE

There are three alternatively spliced PTEN mRNAs, producing proteins differing by a few amino acids at their carboxyl termini (Smith, 1999 and Goberdhan, 1999)

Transcript length - 2.2 kb

Bases in 5' UTR - 527

Exons - 12

Bases in 3' UTR - 921


PROTEIN STRUCTURE

Amino Acids - 509

Structural Domains

The predicted Pten protein was aligned and compared with other known PTEN homologs. The amino-terminal half of the Drosophila Pten protein has been particularly highly conserved over evolution, sharing ~65% identity with human PTEN in this region and ~40% and 30% identity, respectively, with the more divergent Caenorhabditis elegans (Ogg. 1998) and yeast (L. Li, 1997) PTEN homologs. Like its counterparts in other organisms, Drosophila Pten contains a putative protein phosphatase motif within a larger region related to an actin binding domain in the cytoskeletal protein tensin. A number of amino acids shared by all members of the PTEN family are not present in other protein phosphatases or tensin family members. These residues may have an important role in the specific functions of PTEN, such as its phosphoinositide 3-phosphatase activity. Sequence comparison of the carboxy-terminal half of Drosophila Pten with human PTEN also highlights a number of conserved regions, which may be involved in the regulation of this molecule (Goberdhan, 1999).


Pten: Evolutionary Homologs | Regulation | Developmental Biology | Effects of Mutation | References

date revised: 30 March 2013

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