InteractiveFly: GeneBrief

Lowfat: Biological Overview | References

The Fat-Hippo-Warts signaling network regulates both transcription and planar cell polarity. Despite its crucial importance to the normal control of growth and planar polarity, there is only a limited understanding of the mechanisms that regulate Fat. This study reports the identification of a conserved cytoplasmic protein, Lowfat (Lft), as a modulator of Fat signaling. Drosophila Lft, and its human homologs LIX1 and LIX1-like, bind to the cytoplasmic domains of the Fat ligand Dachsous, the receptor protein Fat, and its human homolog FAT4. Lft protein can localize to the sub-apical membrane in disc cells, and this membrane localization is influenced by Fat and Dachsous. Lft expression is normally upregulated along the dorsoventral boundary of the developing wing, and is responsible for elevated levels of Fat protein there. Levels of Fat and Dachsous protein are reduced in lft mutant cells, and can be increased by overexpression of Lft. lft mutant animals exhibit a wing phenotype similar to that of animals with weak alleles of fat, and lft interacts genetically with both fat and dachsous. These studies identify Lft as a novel component of the Fat signaling pathway, and the Lft-mediated elevation of Fat levels as a mechanism for modulating Fat signaling (Mao, 2009).

Recent studies have linked together the action of several tumor suppressors into a Fat-Hippo-Warts signaling network. These genes play a crucial role in growth control from Drosophila to mammals, as exemplified by the ever-increasing number of cancers that have been associated with mutations in pathway genes. Fat-Warts signaling regulates growth through a transcriptional co-activator protein, called Yorkie (Yki) in Drosophila and YAP in vertebrates. In addition, Fat influences a distinct planar cell polarity (PCP) pathway. Planar cell polarity is the polarization of cells within the plane of a tissue, and can include both polarized structures, like hairs and bristles, and polarized behaviors, such as cell division and cell intercalation (Mao, 2009).

Fat is a large member of the cadherin family, and acts as a transmembrane receptor. Fat influences the subcellular localization of both the unconventional myosin Dachs and the FERM-domain protein Expanded, and through these proteins ultimately regulates the kinase Warts. Warts then inhibits Yki by phosphorylating it: phosphorylated Yki is retained in the cytoplasm, but unphosphorylated Yki enters the nucleus to promote the transcription of target genes. The Fat PCP pathway is less well characterized, but it is partially dependent upon Dachs, and also involves Atrophin (Grunge), a transcriptional co-repressor that can bind to the Fat cytoplasmic domain (Mao, 2009).

The only Fat ligand identified is Dachsous (Ds), which like Fat is a large, atypical cadherin, and which influences the phosphorylation of Fat by Discs overgrown. ds mutants have phenotypes similar to, but weaker than, those of fat mutants, raising the possibility that there might be other ligands, or other means of regulating Fat. The Golgi kinase Four-jointed (Fj) also regulates Fat signaling, but presumably acts by modulating Fat-Ds interactions. Intriguingly, the two known Fat pathway regulators (ds and fj) are expressed in gradients in developing tissues. The vectors (directions) of these gradients parallel vectors of PCP, and experimental manipulations of ds and fj indicate that, at least in some tissues, their graded expression can direct PCP. The graded expression of ds and fj also influences the transcriptional branch of the pathway and wing growth, but in this case it is the slope rather than the vector of their gradients that appears to be instructive (Mao, 2009).

Although thus far most components of Fat signaling have been identified through genetic studies in Drosophila, protein interaction screens are an alternative approach with which to identify components of signaling pathways. A genome-wide yeast two-hybrid screen identified the product of the CG13139 gene as both a candidate Fat-interacting protein and a candidate Ds-interacting protein. This gene, which has been named lowfat (lft), encodes a small protein of unknown structure and biochemical function. It shares sequence similarity with two vertebrate genes, Limb expression 1 (Lix1) and Lix1-like (Lix1l;. Lix1 was first identified in chickens through a differential screen for genes expressed during early limb development. Subsequent analysis in mice revealed that Lix1 is actually expressed more broadly (Moeller, 2002). Lix1l has been defined only by its sequence similarity to Lix1. The biological functions of these genes have not been described, although genetic mapping of a feline spinal muscular atrophy identified LIX1 (Fyfe, 2006) as a candidate gene (Mao, 2009).

While a basic outline of Fat signaling has emerged, many steps remain poorly understood. This study shows that lft is a modulator of Fat signaling, and identified a cellular requirement for Lft in establishing normal levels of both Fat and Ds. These observations identify transcriptional regulation of lft as a potential mechanism for modulating Fat signaling through its post-translational regulation of Fat and Ds protein levels. It was also establish human LIX1L as a functional homolog of Lft, and LIX1 and LIX1L were shown to be Fat-interacting proteins, thus identifying a likely cellular function of vertebrate Lix1 genes as modulators of Fat signaling. This linkage raises the possibility that other Fat pathway components could be candidate susceptibility loci for spinal muscular atrophy (Mao, 2009).

lft mutants display decreased levels of both Fat and Ds protein staining, and presumably as a consequence exhibit a characteristic Fat pathway phenotype in the wing. In addition, lft can genetically interact with both fat and ds to cause more severe phenotypes. The lft mutant phenotype resembles weak mutant alleles of fat or ds, and lft mutants do not exhibit any additional phenotypes that could not be accounted for by effects on Fat signaling. The expression of lft itself is modulated by other signaling pathways, and differences in lft expression levels correlate with differences in Fat and Ds protein levels both in wild-type animals, and when lft levels are experimentally increased or decreased. Thus, transcriptional regulation of lft defines a mechanism for modulating Fat signaling (Mao, 2009).

Lft influences levels of both Fat and Ds. Because Fat and Ds in turn can influence levels of Lft, and because Fat and Ds also influence the localization of one another to the membrane, it is inferred that for any one of these three proteins, the influence that it has on the other two includes both direct effects, and indirect effects mediated through the third protein. In addition, the net effect observed for any one protein presumably also reflects the consequences of feedback regulation of its own levels via the other two proteins (Mao, 2009).

Given the substantial decrease in Fat staining in lft mutants, the phenotype appears surprisingly mild. This observation suggests that Fat is normally present in excess; for example, it could be that only a fraction of Fat is normally active, and that levels of Fat are not normally limiting for pathway activation. This hypothesis was supported by the observation of enhanced Fat pathway phenotypes in combination with fat¹, and would be consistent with the conclusion that Fat acts as a ligand-activated receptor, with only a fraction of Fat normally being present in the active form (Feng, 2009; Sopko, 2009). Complicating this simple explanation is the observation that the levels of the Fat ligand Ds are also reduced in lft mutants. However, because Fat signaling is influenced not only by the amount of Ds, but also by the pattern of Ds (i.e. is Ds expression graded, and how steeply), Ds can have positive or negative effects on Fat activity. Thus, it is suggested that the lft mutant phenotype might be relatively weak because decreased Fat and Ds levels, which would be expected to decrease Fat signaling, are partially offset by a flattening of the Fat and Ds expression gradients, which would be expected to increase Fat-Warts signaling (Reddy, 2008; Rogulja, 2008; Willecke, 2008; Mao, 2009 and references therein).

The observation that ds lft double mutants have more severe phenotypes than do ds or lft single mutants indicates that ds and lft can each independently influence Fat. lft and ds both influence Fat levels and localization, but even in the absence of these two genes, there was a visible difference in Fat protein staining between the wing pouch and the wing hinge. This implies that there are additional Fat regulators, and that the expression of these additional Fat regulators is differentially distributed between the wing pouch and the wing hinge. One additional Fat regulator that is differentially expressed between the pouch and the hinge is Fj, although as Fj is thought to act by influencing Fat-Ds interactions, it is not clear whether it could explain the differential Fat staining observed (Mao, 2009).

It appears that Lft is a major contributor to the normal levels of Fat. Since Lft binds to the Fat cytoplasmic domain, it presumably influences Fat protein levels through this direct binding. Different molecular mechanisms for how Lft might influence Fat (and Ds) levels can be envisioned. One attractive possibility, given that Fat and Ds are transmembrane proteins, and that Lft could co-localize with them at the sub-apical membrane, is an effect on endocytosis, but it is also possible that Lft affects them in some other way (Mao, 2009).

Because Lft is closely related to LIX1 and LIX1L, and indeed LIX1L is functionally homologous to Lft, these studies of Lft identify regulation of mammalian Fat and Ds homologs as the likely cellular functions of LIX1 and LIX1L. Consistent with this inference, these proteins could bind to the cytoplasmic domain of human FAT4, and a BLASTP search with a short sequence motif of Fat common to Ds and FAT4 (WEYLLNWGPSYENLMGVFKDIAELPD) identifies these three proteins plus the mammalian Ds homologs DCHS1 and DCHS2 as the five closest matches in protein databases. This sequence motif also exhibits weak similarity to a region of E-cadherin that has been identified as contributing to binding to β-catenin, but there is no obvious primary sequence similarity between Lft and β-catenin, and Lft did not detectably affect E-cadherin staining (Mao, 2009).

Functional studies of LIX1 and LIX1L in vertebrates have not yet been reported. However, feline LIX1 has been genetically linked to feline spinal muscular atrophy (Fyfe, 2006). Direct examination of human LIX1 in spinal muscular atrophy patients did not reveal any mutations. Nonetheless, the linkage of LIX1 and LIX1L to Fat signaling suggests that other members of the Fat signaling pathway should also be examined as potential candidate susceptibility loci for this debilitating disease. Murine Fat4 has been shown to be required for normal PCP in the ear and kidney; however, it is also highly expressed in the nervous system, as are murine Lix1 and Dchs genes, consistent with the expectation that these genes will interact in mammals, and might influence nervous system development (Mao, 2009).

Two frizzled planar cell polarity signals in the Drosophila wing are differentially organized by the Fat/Dachsous pathway

The regular array of distally pointing hairs on the mature Drosophila wing is evidence for the fine control of Planar Cell Polarity (PCP) during wing development. Normal wing PCP requires both the Frizzled (Fz) PCP pathway and the Fat/Dachsous (Ft/Ds) pathway, although the functional relationship between these pathways remains under debate. There is strong evidence that the Fz PCP pathway signals twice during wing development, and a Bidirectional-Biphasic Fz PCP signaling model has been presented which proposes that the Early and Late Fz PCP signals are in different directions and employ different isoforms of the Prickle protein. The goal of this study was to investigate the role of the Ft/Ds pathway in the context of the Fz PCP signaling model. The results lead to the following conclusions: (1) The Early Fz PCP signals are in opposing directions in the anterior and posterior wing and converge precisely at the site of the L3 wing vein. (2) Increased or decreased expression of Ft/Ds pathway genes can alter the direction of the Early Fz PCP signal without affecting the Late Fz PCP signal. (3) Lowfat (Lft), a Ft/Ds pathway regulator, is required for the normal orientation of the Early Fz PCP signal but not the Late Fz PCP signal. (4) At the time of the Early Fz PCP signal there are symmetric gradients of dachsous (ds) expression centered on the L3 wing vein, suggesting Ds activity gradients may orient the Fz signal. (5) Localized knockdown or over-expression of Ft/Ds pathway genes shows that boundaries/gradients of Ft/Ds pathway gene expression can redirect the Early Fz PCP signal specifically. (6) Altering the timing of ds knockdown during wing development can separate the role of the Ft/Ds pathway in wing morphogenesis from its role in Early Fz PCP signaling (Hogan, 2011).

The data presented in this report allow refinement Bidirectional-Biphasic (Bid-Bip) Fz PCP signaling model, particularly the nature of the proposed Early Fz(Sple) signal (Sple is an isoform of Prickle). The Early Fz(Sple) signal is in opposing directions in the anterior and posterior wing and converges precisely at the site of the L3 vein. The site of the L3 vein, therefore, represents a discontinuity in Early Fz(Sple) signaling that is called the PCP-D (see A model for PCP specification in the Drosophila wing). However, it is clear that physical differentiation of the L3 vein is not required for the formation of the PCP discontinuity (PCP-D). The correspondence of the PCP-D with the site of the L3 vein is perhaps surprising as the compartment boundary (a barrier to clonal growth that runs a few cells anterior to the L4 vein) appears a more obvious boundary between the anterior and posterior wing. However, the L3 vein has been defined as a specific region of low Hedgehog signaling within the wing, suggesting this region has the molecular autonomy needed to function as a signaling centre. In addition, recently published work from the Eaton lab (Aigouy, 2010) has also identified the L3 vein as the boundary between oppositely polarized cells in the anterior and posterior of early pupal wings (Hogan, 2011).

Both reduced activity and uniform over-expression of Ft/Ds pathway genes have similar effects on the direction of the Fz(Sple) signal, which becomes more distal in both the anterior wing and distal regions of the posterior wing. Significantly, the Eaton lab has shown that the subcellular localization of Vang/Stbm protein in the early (15 hours a.p.f.) pupal wing of a ds mutant is more distal than wild-type in both the anterior and distal posterior wing (Aigouy, 2010). The current results are consistent with the idea that the normal direction of the Fz(Sple) signal is controlled by gradients of Ft/Ds pathway activity that can be flattened through either reduced or uniform expression of individual pathway components. An observation made by Matakatsu (2004) that ds is expressed transiently in a P-D stripe within the pupal wing blade at around the time of Early Fz PCP signaling and the peak of Ds expression has been localized to the site of the L3 vein, the same location as the wing PCP-D. This implies that there are symmetric gradients of ds expression in the anterior and posterior wing and that the Early Fz(Sple) signal points up a ds expression gradient. This conclusion is supported by the finding that the Fz(Sple) signal reorients to point away from localized ds knockdown, but not from localized ds over-expression. The Early Fz(Sple) signal also points away from over-expressed ft or fj, which suggests that Ft or Fj activity has the opposite effect to Ds activity on direction of the Fz(Sple) signal. This is the same relationship between Ft, Ds and Fj activity that has been established in the Drosophila eye. Recent molecular studies have shown that Fj, a golgi kinase, can phosphorylate cadherin domains within both Ft and Ds proteins. It has been proposed that this modification increases Ft activity, but decreases Ds activity (Hogan, 2011).

Reducing ds expression (or increasing ft or fj expression) under the control of the sal-Gal4 driver redirects the Early Fz(Sple) signal for a significant distance (ten or more cell diameters) beyond the sal-Gal4 expression domain. In principle, reducing ds expression within the sal-Gal4 domain should generate a local reversal of the ds expression gradient at the boundary of sal-Gal4 expression (e.g. the L2 vein). This short reversed ds gradient should generate a correspondingly short region of reversed Fz(Sple) signal which should be visible (on a pk^pk mutant wing) as a short region of reversed hair polarity adjacent to the L2 vein. Therefore, the propagation of reversed hair polarity significantly anterior to the L2 vein is surprising. However, a similar propagation of reversed polarity is seen adjacent to loss-of-function and over-expression clones of ds, ft or fj in the Drosophila abdomen. The model proposed for the propagation of altered polarity in the abdomen may, therefore, also apply to the Early Fz(Sple) signal in the wing (Hogan, 2011).

Since it has been established that wing hair polarity points down a gradient of Fz activity and it is proposed that the direction of the Early Fz(Sple) signal (i.e. the hair polarity that would be specified by the signal) points up a Ds expression gradient, it appears that there are opposing gradients of Ds and Fz activity during Early Fz(Sple) signaling. This relationship between Ds and Fz gradients is consistent with that described in the Drosophila eye, although it is opposite to that previously proposed in the wing. These findings, therefore, may help resolve this discrepancy between the proposed relationships of Fz and Ds activity in the eye and wing that has been highlighted by others (Hogan, 2011).

From this work it is concluded that for substantial regions of the wing (including most of the anterior wing and distal regions of the posterior wing), Ft/Ds pathway activity can be altered such that the Early Fz(Sple) signal is redirected, but the Late Fz(Pk) signal remains unaffected. For any specific experiment, this result might be explained by the specific properties of the mutant allele used or by the specific spatial or temporal activity of the Gal4 driver used to drive gene knockdown or over-expression. However, this study has shown that numerous alleles, as well as both knockdown and over-expression, of Ft/Ds pathway genes, can redirect the Fz(Sple) signal in a similar way, without affecting the Fz(Pk) signal in the same region. This suggests that across most of the wing there is a different requirement for the Ft/Ds pathway in the Early Fz(Sple) and Late Fz(Pk) signals. Moreover, it was found that loss of the Ft/Ds pathway regulator Lft affects the Early Fz(Sple) signal, but not the Late Fz(Pk) signal. This suggests that the mechanism used by the Ft/Ds pathway to direct the Early Fz(Sple) signal differs from that used to organize the Late Fz(Pk) signal (Hogan, 2011).

What, then, is the role of the Ft/Ds pathway in the Late Fz(Pk) signal? Since the Late Fz(Pk) signal organizes hair polarity, characterizing the loss of Ft/Ds pathway activity on hair polarity should be informative. It was found that driving ft or ds RNAi uniformly in the wing results in altered wing morphology, but only localized proximal hair polarity changes. This might be due to incomplete gene knockdown, coupled with different requirements for Ft/Ds activity for Late Fz PCP signaling in different regions of the wing. However, it is suggestive that wings homozygous for a fj amorphic allele show only a localized hair polarity phenotype in this same proximal region, implying that Fj is only required for hair polarity in the proximal wing. These results raise the possibility the Ft/Ds pathway is normally only required for hair polarity in the proximal wing (Hogan, 2011).

Since neither ft nor ds null flies are adult viable, previous studies have inferred the role of Ft and Ds in wing hair polarity from analyzing phenotypes of viable hypomorphic alleles, clones of amorphic alleles and localized over-expression. Some hypomorphic ds allele combinations display extensive wing hair polarity disruptions, although the residual activity of these specific alleles has not been well characterized. Wing clones homozygous for amorphic ft or ds alleles can show hair phenotypes, although this is dependent upon the position and/or size of the clone. However, mutant clones generate ectopic Ft or Ds activity boundaries/gradients in the wing and it is known that localized mis-expression of Ft/Ds pathway genes can generate hair phenotypes in wing regions not affected by uniform over-expression. Most telling, clones of fj affect hair polarity in regions of the wing that are not affected in amorphic fj wings. These results clearly show that mis-regulated Ft/Ds activity can change wing hair polarity. However, they do not definitively establish a role for Ft/Ds pathway in the normal organization of hair polarity outside of the proximal wing. Therefore, it remains possible that Ft/Ds pathway activity is only required for hair polarity in the proximal wing, but mis-regulated Ft/Ds pathway activity can induce changes in hair polarity in other wing regions. This may restrict the normal role of the Ft/Ds pathway to organizing the Late Fz(Pk) signal in the proximal wing alone (Hogan, 2011).

According to the Bid-Bip model, the two Fz PCP signaling events aligned with different axes of the developing wing allow membrane ridges to be organized in different directions in the anterior and posterior. The ability of the insect wing to deform specifically is vital for insect flight and it has been proposed that wing membrane structure helps provide the appropriate wing rigidity and flexibility. In the case of membrane ridges, the membrane should be flexible parallel to the ridges, but be resistant to folding perpendicular to the ridges. The A-P ridges in the anterior wing are perpendicular to longitudinal wing veins which suggests a rigid anterior wing structure, whereas the posterior ridges are almost parallel with longitudinal wing veins suggesting a more flexible posterior wing structure. This organization is typical for Dipteran wings which usually have a well-supported leading edge and a flexible trailing edge. Indeed, similar ridge organization have been seen in wings of other Drosophila species. Therefore, the different orientation of ridges in the anterior and posterior wing may have a functional basis. The reason for the uniform distal hair polarity across the Drosophila wing is not well understood, but is conserved in a wide range of Dipteran species suggesting a functional constraint. Therefore, the two Fz PCP signals in different directions during Drosophila wing development may provide a mechanism that allows hairs and ridges to be organized appropriately using a single signaling pathway (Hogan, 2011).

Are multiple Fz PCP signaling events active in other Drosophila tissues besides the developing wing? Intriguingly, the Prickle isoforms, Pk and Sple, play different roles in PCP in numerous Drosophila tissues, including the wing, eye, abdomen and leg. This raises the possibility that there are multiple Fz PCP signals involving differential use of Pk and Sple isoforms in each of these tissues. However, the specific phenotypes associated with loss of either or both isoforms within the different tissues suggest that the details of the Bid-Bip model are unlikely to hold true for all tissues. How can multiple Fz PCP signals occur in different directions in the same developing tissue? One possibility is that changes in the molecular makeup of the Fz PCP pathway allow it to respond to different global signals within the tissue, or to respond in different ways to the same global signal. In the Drosophila wing, this might result from the differential use of the Pk and Sple isoforms. Alternatively, the individual Fz PCP signals may respond to different global signals present at different times during tissue development or to a single dynamic global cue. The significance of Prickle isoform switching and the possibility of dynamic global PCP signals are ongoing topics of interest (Hogan, 2011).

Lowfat, a mammalian Lix1 homologue, regulates leg size and growth under the Dachsous/Fat signaling pathway during tissue regeneration

In the cricket Gryllus bimaculatus, missing distal parts of amputated legs are regenerated from blastemas based on positional information. The Dachsous/Fat (Ds/Ft) signaling pathway regulates blastema cell proliferation and positional information along the longitudinal axis during leg regeneration. This study shows that the Gryllus homologue of Lowfat (Gb'Lft), which modulates Ds/Ft signaling in Drosophila, is involved in leg regeneration. Gb'lft is expressed in regenerating legs, and RNAi against Gb'lft (Gb'lft^RNAi) suppresses blastema cell hyperproliferation caused by Gb'ft^RNAi or Gb'ds^RNAi but enhances that caused by Gb'kibra^RNAi or Gb'warts^RNAi. In Gb'lft^RNAi nymphs, missing parts of amputated legs were regenerated, but the length of the regenerated legs was shortened depending on the position of the amputation. Both normal and reversed intercalary regeneration occurred in Gb'lft^RNAi nymphs, suggesting that Gb'Lft is involved in blastema cell proliferation and longitudinal leg regeneration under the Ds/Ft signaling pathway, but it is not required for intercalary regeneration (Bando, 2011).

Dachsous-dependent asymmetric localization of Spiny-legs determines planar cell polarity orientation in Drosophila>

In Drosophila, planar cell polarity (PCP) molecules such as Dachsous (Ds) may function as global directional cues directing the asymmetrical localization of PCP core proteins such as Frizzled (Fz). However, the relationship between Ds asymmetry and Fz localization in the eye is opposite to that in the wing, thereby causing controversy regarding how these two systems are connected. This study shows that this relationship is determined by the ratio of two Prickle (Pk) isoforms, Pk and Spiny-legs (Sple). Pk and Sple form different complexes with distinct subcellular localizations. When the amount of Sple is increased in the wing, Sple induces a reversal of PCP using the Ds-Ft system. A mathematical model demonstrates that Sple is the key regulator connecting Ds and the core proteins. This model explains the previously noted discrepancies in terms of the differing relative amounts of Sple in the eye and wing (Ayukawa, 2014).

The orientation of Fz localization relative to the Ds/Fj gradients (the Ds/Ft asymmetries) in the Drosophila wing is opposite to Fz orientation in the eye. This observation has been a puzzle in the PCP field and a barrier to understanding how the Ds-Ft system and PCP core protein asymmetries are connected. The current experiments and computational simulations have demonstrated that it is the Pk:Sple ratio that governs the relationship between the Ds/Ft asymmetries and core protein localization in the Drosophila eye and wing. Importantly, this model is supported by a loss-of-function experiment in the eye from a previous study. The pksple mutant, which shows specific loss of the Sple isoform, exhibits a polarity reversal in the orientation of the eye ommatidia. The pkpk mutant does not exhibit a complete reversal of PCP in the wing, perhaps because the remaining endogenous amount of Sple is small and/or the timing of expression of endogenous sple is altered. These data reinforce the conclusion that skewing the Pk:Sple ratio alters PCP establishment in the wing and eye (Ayukawa, 2014).

It is hypothesized that tissues in which Sple complexes (Sple-Pk and Sple-Sple) are predominant will tend to have one polarity, whereas tissues containing mainly Pk complexes will show the opposite polarity. However, the possibility that uncomplexed Pk and Sple molecules may influence PCP determination even if Pk-Pk, Sple-Pk, and Sple-Sple complexes localize asymmetrically in each cell cannot be excluded. Alternatively, multimeric protein complexes containing multiple Pk and/or Sple molecules may be responsible for establishing PCP (Ayukawa, 2014).

This study has found that, in tissues where Sple was relatively abundant, Sple (or the Sple complex) was recruited at the cell edge exhibiting the highest Ds level. Furthermore, biochemical and genetic experiments suggested a model in which Sple-Ds cooperation polarizes Sple (or Sple complexes) at the cell edge exhibiting the highest Ds level. It was also demonstrated that the atypical myosin Dachs is heavily involved in the process of Sple polarization in the wing. This observation is intriguing because dachs loss of function does not show a PCP defect as strongly as that of ds or ft loss of function in Drosophila tissues and Dachs does not appear to be as important to PCP in the eye as in the wing. There may be a redundant unknown mechanism responsible for Sple asymmetry (Ayukawa, 2014).

Intriguingly, in the wing of the pkpk mutant, loss of lowfat (lft), one of the members of the Ds-Ft group, affects wing hair polarity in a manner similar to loss of ds or ft. This is despite the fact that, in contrast to the ds or ft mutant, the lft mutant does not show any PCP defect in Drosophila tissues including the wing and eye. These observations are consistent with result showing that Dachs is involved in Sple asymmetry. These results have profound implications regarding the relationship between Pk isoforms and the Ds-Ft system. In addition, this study revealed that Pk physically and genetically interacts with Dachs, even though the subcellular localizations of these two proteins are opposite. There are several possibilities to explain the physiological relevance of the Pk-Dachs interaction. For example, Pk and Sple-Dachs complexes may have mutually antagonistic functions at the opposite cell edges, which is similar to the relationship between Pk (which is localized at the proximal cell border) and Dsh and Dgo (which are localized distally). To understand the molecular mechanism governing global PCP patterning, it will be important to elucidate (1) whether and/or how Dachs is involved in Sple-Ds cooperation/interaction and (2) how Pk becomes engaged in Dachs function and vice versa (Ayukawa, 2014).

Although these experiments do not directly reveal the molecular mechanism by which polarized Sple complexes regulate the asymmetry of the core proteins, a mathematical model was developed based on this study that supports the proposed mechanism governing the core protein asymmetry. The model includes a possible reaction where Sple stabilizes the membrane localization of Stbm on the cell edge with the highest Ds level. An alternative possibility is that, in addition to the above mechanism, Sple directly promotes the formation of the Fz asymmetry via reversing the direction of Fz transport, by changing the orientation of the microtubule array. Future work will include elucidating the molecular mechanism by which the Pk:Sple ratio regulates the core protein asymmetry, as well as determining how the Pk:Sple ratio is differentially regulated in various tissues (Ayukawa, 2014).

Search PubMed for articles about Drosophila Lowfat

Aigouy, B., et al. (2010). Cell flow reorients the axis of planar polarity in the wing epithelium of Drosophila. Cell 142: 773-786. PubMed ID: 20813263

Ayukawa, T., Akiyama, M., Mummery-Widmer, J. L., Stoeger, T., Sasaki, J., Knoblich, J. A., Senoo, H., Sasaki, T., Yamazaki, M. (2014) Dachsous-dependent asymmetric localization of Spiny-legs determines planar cell polarity orientation in Drosophila. Cell Rep. 8(2):610-21. PubMed ID: 24998533

Bando, T., et al. (2011). Lowfat, a mammalian Lix1 homologue, regulates leg size and growth under the Dachsous/Fat signaling pathway during tissue regeneration. Dev. Dyn. 240(6): 1440-53. PubMed ID: 21538682

Feng, Y. and Irvine, K. D. (2009). Processing and phosphorylation of the Fat receptor. Proc. Natl. Acad. Sci. 106: 11989-11994. PubMed ID: 19574458

Fyfe, J. C., Menotti-Raymond, M., David, V. A., Brichta, L., Schaffer, A. A., Agarwala, R., Murphy, W. J., Wedemeyer, W. J., Gregory, B. L., Buzzell, B. G. et al. (2006). An approximately 140-kb deletion associated with feline spinal muscular atrophy implies an essential LIX1 function for motor neuron survival. Genome Res. 16: 1084-1090. PubMed ID: 16899656

Hogan, J., Valentine, M., Cox, C., Doyle, K. and Collier, S. (2011). Two frizzled planar cell polarity signals in the Drosophila wing are differentially organized by the Fat/Dachsous pathway. PLoS Genet. 7(2): e1001305. PubMed ID: 21379328

Mao, Y., Kucuk, B. and Irvine, K. D. (2009). Drosophila lowfat, a novel modulator of Fat signaling. Development 136(19): 3223-33. PubMed ID: 19710173

Matakatsu, H. and Blair, S. S. (2004). Interactions between Fat and Dachsous and the regulation of planar cell polarity in the Drosophila wing. Development 131: 3785-3794. PubMed ID: 15240556

Moeller, C., Yaylaoglu, M. B., Alvarez-Bolado, G., Thaller, C. and Eichele, G. (2002). Murine Lix1, a novel marker for substantia nigra, cortical layer 5, and hindbrain structures. Brain Res. Gene Expr. Patterns 1: 199-203. PubMed ID: 12638132

Reddy, B. V. and Irvine, K. D. (2008). The Fat and Warts signaling pathways: new insights into their regulation, mechanism and conservation. Development 135: 2827-2838. PubMed ID: 18697904

Rogulja, D., Rauskolb, C. and Irvine, K. D. (2008). Morphogen control of wing growth through the Fat signaling pathway. Dev. Cell 15: 309-321. PubMed ID: 18694569

Sopko, R., Silva, E., Clayton, L., Gardano, L., Barrios-Rodiles, M., Wrana, J., Varelas, X., Arbouzova, N. I., Shaw, S., Saburi, S. et al. (2009). Phosphorylation of the tumor suppressor fat is regulated by its ligand Dachsous and the kinase discs overgrown. Curr. Biol. 19: 1112-1117. PubMed ID: 19540118

Willecke, M., Hamaratoglu, F., Sansores-Garcia, L., Tao, C. and Halder, G. (2008). Boundaries of Dachsous Cadherin activity modulate the Hippo signaling pathway to induce cell proliferation. Proc. Natl. Acad. Sci. 105: 14897-14902. PubMed ID: 18809931

date revised: 23 August 2014

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