The DYRKs (dual specificity tyrosine phosphorylation-regulated kinases) are a conserved family of protein kinases that autophosphorylate a tyrosine residue in their activation loop by an intra-molecular mechanism and phosphorylate exogenous substrates on serine/threonine residues. Little is known about the identity of true substrates for DYRK family members and their binding partners. To address this question, full-length dDYRK2 (Drosophila DYRK2) was used as bait in a yeast two-hybrid screen of a Drosophila embryo cDNA library. Of 14 independent dDYRK2 interacting clones identified, three were derived from the chromatin remodelling factor, SNR1 (Snf5-related 1), and three from the essential chromatin component, TRX (trithorax). The association of dDYRK2 with SNR1 and TRX was confirmed by co-immunoprecipitation studies. Deletion analysis showed that the C-terminus of dDYRK2 modulated the interaction with SNR1 and TRX. DYRK family member MNB (Minibrain) was also found to co-precipitate with SNR1 and TRX, associations that did not require the C-terminus of the molecule. dDYRK2 and MNB were also found to phosphorylate SNR1 at Thr102 in vitro and in vivo. This phosphorylation required the highly conserved DH-box (DYRK homology box) of dDYRK2, whereas the DH-box was not essential for phosphorylation by MNB. This is the first instance of phosphorylation of SNR1 or any of its homologues and implicates the DYRK family of kinases with a role in chromatin remodelling (Kinstrie, 2006. Full text of article).

Minibrain/Dyrk1a regulates food intake through the Sir2-FOXO-sNPF/NPY pathway in Drosophila and mammals

Feeding behavior, one of the most essential activities in animals, is tightly regulated by neuroendocrine factors. Drosophila short neuropeptide F (sNPF) and the mammalian functional homolog neuropeptide Y (NPY) regulate food intake. Understanding the molecular mechanism of sNPF and NPY signaling is critical to elucidate feeding regulation. This study found that minibrain (mnb) and the mammalian ortholog Dyrk1a, target genes of sNPF and NPY signaling, regulate food intake in Drosophila and mice. In Drosophila neuronal cells and mouse hypothalamic cells, sNPF and NPY modulated the mnb and Dyrk1a expression through the PKA-CREB pathway. Increased Dyrk1a activated Sirt1 to regulate the deacetylation of FOXO, which potentiated FOXO-induced sNPF/NPY expression and in turn promoted food intake. Conversely, AKT-mediated insulin signaling suppressed FOXO-mediated sNPF/NPY expression, which resulted in decreasing food intake. Furthermore, human Dyrk1a transgenic mice exhibited decreased FOXO acetylation and increased NPY expression in the hypothalamus, and increased food intake. These findings demonstrate that Mnb/Dyrk1a regulates food intake through the evolutionary conserved Sir2-FOXO-sNPF/NPY pathway in Drosophila and mammals (Hong, 2012).

The production of sNPF and NPY in sNPFnergic and hypothalamic neurons of flies and mammals respectively, is increased during fasting. These neuropeptides are secreted to produce paracrine and endocrine effects but also feedback upon their synthesizing neurons where they respectively induce mnb and Dyrk1a gene expression through the PKA-CREB pathway. This Mnb/Dyrk1a kinase phosphorylates and activates the Sir2/Sirt1 deacetylase, which in turn deacetylates and activates the FOXO transcription factor. Among its many potential targets, FOXO then increases sNPF/NPY mRNA expression. Negative controls modulate the positive feedback of sNPF/NPY. Feeding activates the insulin receptor-PI3K-AKT pathway. FOXO becomes phosphorylated and transcriptionally inactivated by translocation to the cytoplasm. In this state the induction of sNPF/NPY by FOXO is decreased. Because sNPF and NPY are orexogenic, their positive feedback during fasting should reinforce the propensity for food intake whereas the negative regulation of sNPF and NPY mRNA during feeding condition would then contribute to satiety (Hong, 2012).

FOXO family transcriptional factors are involved in metabolism, longevity, and cell proliferation. FOXO is in part regulated in these processes by post-transcriptional modifications including phosphorylation and acetylation. In many model systems, the ligand activated Insulin-PI3K-AKT pathway phosphorylates FOXO to inactivate this transcription factor by moving it to the cytoplasm. The cytoplasmic localization of FOXO is mediated by 14-3-3 chaperone proteins in Drosophila and mammals. FOXO may also be acetylated, as is FoxO1 of mice, by the CREB-binding protein (CBP)/p300 acetylase and this inhibits FOXO transcriptional function by suppressing its DNA-binding affinity. Such FoxO1 acetylation can be reversed by SirT1 to help activate the FoxO1 transcription factor. This study describes for Drosophila how dFOXO in sNPFR1 neurons regulates the expression of sNPF and food intake. This mechanism parallels how hypothalamic FoxO1 regulates food intake through its control of orexigenic NPY and Agrp in rodents. Post-transcriptional modification of FOXO is central to these controls in both animals. sNPF and NPY expression is increased when FOXO is deacetylated by Sir2/Sirt1, while sNPF and NPY are decreased when FOXO is phosphorylated via the Insulin-PI3K-AKT pathway. Post-transcriptional modifications of FOXO proteins play a critical role for controlling food intake through the sNPF and NPY expression in flies and rodents (Hong, 2012).

Mnb/Dyrk1a participate in olfactory learning, circadian rhythm, and the development of the nervous system and brain. Mnb and Dyrk1a proteins contain a nuclear targeting signal sequence, a protein kinase domain, a PEST domain, and a serine/threonine rich domain. The kinase domains are evolutionary well-conserved from flies to humans. In Down syndrome (DS), chromosome 21 trisomy gives patients three copies of a critical region that includes the Mnb/Dyrk1a; trisomy of this region is associated with anomalies of both the nervous and endocrine systems. DS patients often show high Body Mass Index due to the increased fat mass. Children with DS have elevated serum leptin coupled with leptin resistance, both of which contribute to the obesity risk common to DS patients. This study found a novel function of Mnb/Dyrk1a that may underlay this metabolic condition of DS patients. Mnb/Dyrk1a regulates food intake in flies and mice. This is controlled by sNPF/NPY-PKA-CREB upstream signaling and thus produces downstream affects upon Sir2/Sirt1-FOXO-sNPF/NPY. Fasting not only increases the expression of mnb, but also of sNPF, suggesting that Mnb kinase activates a positive feedback loop where Sir2-dFOXO induces sNPF gene expression. Notably, fasting increases Sirt1 deacetylase activity and localizes FoxO1 to the nucleus in the orexogenic AgRP neurons of the mouse hypothalamus. Increased dosage of Dyrk1a in DS patients may reinforce the positive feedback by NPY and disrupt the balance between hunger and satiety required to maintain a healthy body mass (Hong, 2012).

Insulin produced in the pancreas affects the hypothalamus to regulate feeding in mammals. Insulin injected into the intracerebroventrical of the hypothalamus reduces food intake while inhibiting insulin receptors of the hypothalamic ARC nucleus causes hyperphasia and obesity in rodent models. This study showed a similar pattern for Drosophila where overexpression of insulin-like peptide (Dilp2) at insulin producing neurons decreased food intake while food intake was increased by inhibiting the insulin receptor in sNPFR1 expressing neurons. Likewise, during fasting, serum insulin and leptin levels are decreased in mammals, as is mRNA for insulin-like peptides of Drosophila. Thus, the mechanism by which insulin and insulin receptor signaling suppresses food intake is conserved from fly to mammals in at least some important ways (Hong, 2012).

Previous work has shown how sNPF signaling regulates Dilp expression through ERK in IPCs and controls growth in Drosophila (Lee, 2008). This study shows that sNPF signaling regulates mnb expression through the PKA-CREB pathway in non-IPC neurons and controls food intake. Since sNPF works through the sNPFR1 receptor, sNPFR1 in IPCs and non-IPCs neurons might transduce different signals and thereby modulate different phenotypes. Four Dilps (Dilp1, 2, 3, and 5) are expressed in the IPCs of the brain. Interestingly, levels of Dilp1 and 2 mRNA are reduced in the sNPF mutant, which has small body size, but this study finds only Dilp3 and 5 mRNA levels are reduced upon 24 h fasting. Likewise, only Dilp5 is reduced when adult flies are maintained on yeast-limited diets. In addition, Dilp1 and 2 null mutants show slight reduced body weights but Dilp3 and Dilp5 null mutants do not. These results suggest that Dilp1 and 2 behave like a mammalian insulin growth factor for size regulation while Dilp3 and 5 act like a mammalian insulin for the regulation of metabolism. However, in the long term starvation, Dilp2 and Dilp5 mRNA levels are reduced and Dilp3 mRNA expression is increased (Hong, 2012).

During fasting, sNPF but not sNPFR1 mRNA expression was increased in samples prepared from fly heads increasing food intake. In contrast, in feeding, the high level of insulin signaling reduced sNPF but not sNPFR1 mRNA expression and suppresses food intake. Interestingly, in the antenna of starved flies, sNPFR1 but not sNPF mRNA expression is increased and induces presynaptic facilitation, which results in effective odor-driven food search. However, high insulin signaling suppresses sNPFR1 mRNA expression and prevents presynaptic facilitation in DM1 glomerulus. These results indicate that starvation-mediated or insulin signaling-mediated sNPF-sNPFR1 signaling plays a critical role in Drosophila feeding behavior including food intake and food search even though the fine tuning is different (Hong, 2012).

This study presents a molecular mechanism for how sNPF and NPY regulate food intake in Drosophila and mice. A system of positive feedback regulation for sNPF and NPY signaling is described that increases food intake and a mode of negative regulation for sNPF and NPY by the insulin signaling that suppresses food intake. Modifications of the FOXO protein play a critical role for regulating sNPF and NPY expression, resulting in the control of food intake (Hong, 2012).

Riquiqui and Minibrain are regulators of the Hippo pathway downstream of Dachsous

The atypical cadherins Fat (Ft) and Dachsous (Ds) control tissue growth through the Salvador-Warts-Hippo (SWH) pathway, and also regulate planar cell polarity and morphogenesis. Ft and Ds engage in reciprocal signalling as both proteins can serve as receptor and ligand for each other. The intracellular domains (ICDs) of Ft and Ds regulate the activity of the key SWH pathway transcriptional co-activator protein Yorkie (Yki). Signalling from the FtICD is well characterized and controls tissue growth by regulating the abundance of the Yki-repressive kinase Warts (Wts). This study identified two regulators of the Drosophila melanogaster SWH pathway that function downstream of the DsICD: the WD40 repeat protein Riquiqui (Riq) and the DYRK-family kinase Minibrain (Mnb). Ds physically interacts with Riq, which binds to both Mnb and Wts. Riq and Mnb promote Yki-dependent tissue growth by stimulating phosphorylation-dependent inhibition of Wts. Thus, this study describes a previously unknown branch of the SWH pathway that controls tissue growth downstream of Ds (Degoutin, 2013).

The related cadherins Ft and Ds control tissue growth by regulating SWH pathway activity, and also control PCP and morphogenesis. Intriguingly, Ft and Ds regulate SWH pathway activity by engaging in reciprocal signalling as a ligand-receptor pair. Signalling downstream of Ft is reasonably well defined, but signalling downstream of Ds in growth control has remained uncharacterized until the discovery of a membrane-to-nucleus signalling pathway controlling SWH pathway activity downstream of the DsICD, described in this study. Genetic and biochemical data imply that the WD40 repeat protein Riq complexes with the DsICD and can bind to the Mnb and Wts kinases. Riq promotes Mnb-dependent phosphorylation and inhibition of Wts, and thereby promotes Yki-dependent tissue growth. Further investigation is required to define biologically relevant Wts residues that are phosphorylated by Mnb. This study shows that Mnb phosphorylates Wts on several residues in its amino-terminal third, although it is formally possible that other regions of Wts are also phosphorylated by Mnb (Degoutin, 2013).

Therefore, Ds-Ft ligation induces two seemingly opposing growth-regulatory events: Ds activates Ft, which represses Yki by modulating Dachs whereas Ft signals through Ds, Riq and Mnb to activate Yki. At first glance it seems counter-intuitive that Ft-Ds binding would both promote, and repress Yki-dependent tissue growth but raises several interesting possibilities. One option is that the timing of signalling from both the DsICD and the FtICD is different and varies throughout the cell cycle. For example, DsICD might deliver a pulse of Yki activity to induce transcriptional events associated with tissue growth. Subsequently, to ensure that Yki activity does not perdure and cause tissue overgrowth, it could be repressed by signalling from FtICD. Alternatively, DsICD or FtICD signalling might predominate over the other in different regions of imaginal discs or at different stages of development, to regulate Yki. Such regulation could occur through several mechanisms; 1) it could possibly stem from polarized activity of Ft and Ds that occurs in cells of growing imaginal discs in response to graded expression of Ds and Fj, 2) it could occur if the influence of signalling downstream of FtICD or DsICD on Wts activity was quantitatively different, 3) it could result from non-uniform activity of additional proteins that mediate Ft and Ds signalling. Alternatively, repression of Yki by the FtICD, and activation by the DsICD, could quantitatively oppose each other and serve to set a fine threshold of Yki activity that is highly sensitive to regulation by other branches of the SWH pathway such as the Kibra-Ex-Merlin complex, the Hpo activating kinase Tao-1 or apicobasal polarity proteins. In future studies it will be important to define the spatiotemporal activity profile of FtICD and DsICD signalling and the relative influence of the Ds and Ft branches of the SWH pathway on tissue growth (Degoutin, 2013).

Given that Ft and Ds also engage in bi-directional signalling to control PCP and morphogenesis, it will be important to determine whether Riq and Mnb control these processes downstream of the DsICD. In addition, it will be important to investigate whether the signalling events described in this study are conserved in mammals. Interestingly, a reverse regulatory event to that described in this study, between the human orthologues of Wts (LATS2) and Mnb (DYRK1A), has been reported. LATS2 was shown to phosphorylate DYRK1A and promote senescence of cultured cells, raising the possibility that Wts/LATS1/2 and Mnb/DYRK1A/1B kinases engage in mutual regulatory relationships (Degoutin, 2013).

Finally, given the emergence of the SWH pathway as an important regulator of different human tumours, the present study raises the possibility that in a pathological setting the human orthologues of Riq (DCAF7) and Mnb (DYRK1A and DYRK1B) could function as oncogenes. Cell culture studies have provided conflicting reports on whether DYRK1A and DYRK1B act as oncogenes or tumour suppressor genes However, in vivo studies in both flies and mice, and genetic studies in humans, have described only positive roles for Mnb/DYRK1A/DYRK1B in tissue growth: dyrk1a heterozygous mice exhibit growth retardation and impaired brain development, DYRK1A mutations cause microcephaly and growth retardation in humans, whereas Mnb promotes D. melanogaster tissue growth ). These in vivo studies support the possibility that DYRK1A, DYRK1B and DCAF7 could be oncogenic in human cancers (Degoutin, 2013).


Protein extracts of embryos and pupae contain consistently more Mnb protein A and C than those of third instar larvae and adults. By contrast, Mnb protein B appears to be expressed most markedly in third instar larvae and pupae. In addition, Mnb protein B is the most prominent of the three in third instar larvae (Tejedor, 1995).


In late embryos, MNB mRNA is expressed in the ventral cord and in the brain, but not in the peripheral nervous system. Also, MNB mRNA is not detected in embryonic neuroblasts (Tejedor, 1995).


Anti Mnb antibodies stain most prominently the mushroom body neuropil and the opc of the optic lobes. Thus mnb appears to be expressed prominently in larval tissue where neuronal progeny are generated during post-embryonic development. Strikingly, the level of protein is low in adult optic lobes and central brain hemispheres (Tejedor, 1995)


The level of Mnb protein is low in adult optic lobes and central brain hemespheres but relatively high in retinal pigment cells and in the alpha, beta and gama lobes and peduncle of the mushroom bodies (Tejedor, 1995).

Effects of mutation or deletion

Four alleles of minibrain have been described. The external appearance of mutant flies, including body and sensory organs, is nearly indistinguishable from wild type. The mutants are slightly smaller in size and require about 10% more time for their development; they also have considerable difficulties escaping from their pupal case. The brains of adult mutant flies are greatly reduced in size but shows no gross alterations in neuronal architecture. Major size reductions are seen in the optic lobes (50%-70%), most markedly in the lobula complex and in the central brain (40%-50%). The marked reduction of the lobula complex is probably also the reason for the increased curvature of the medulla in mnb mutants. The central brain hemispheres are reduced mainly in their ventral to dorsal and, respectively, anterior and posterior extensions. Axon bundles that project from the lobula complex to the lateral protocerebrum (optic stalk) are visibly thinner in the mutants. The number of anterior optic tract fibers is reduced by about 70%, and the number of cervical connective fibers is reduced by about 30%. Eyes appear normal (Tejedor, 1995).

Freely walking mutant flies cannot fixate a pattern in an area test. Wild type flies are attracted by a vertical dark stripe surrounded by an illuminated translucent area, while mutant flies have lost this preference. Odor discrimination is poor. Although locomotor activity of freely walking animals is low, optomotor turning behavior of mutant males walking on a styrofoam ball and motion-induced landing responses are normal.

minibrain mutant larvae develop normally into the third instar. Mutations cause an abnormal spacing of neuroblasts in the outer proliferation center (opc) of larval brain, with the implication that mnb opc neuroblasts produce less neuronal progeny than do wild type. As a consequence, the adult mnb brain exhibits a specific and marked size reduction of the optic lobes and central brain hemispheres. The insufficient number of distinct neurons in mnb brains is correlated with specific abnormalities in visual and olfactory behavior, although eye and antennal morphology are normal (Tejedor, 1995).

The influence of mutations in seven neurological genes on the number of fibers in the anterior optic tract (AOT) of Drosophila melanogaster has been investigated. The number of fibers in the AOT can be drastically reduced in single and especially in multiple mutants. However, no evidence for synergistic interactions between the sample of mutations used in any of the genes examined (sine oculis , reduced optic lobes, minibrain, and small optic lobes) was obtained at the level of the AOT. The rolKS222 and so mutations eliminate similar fiber sets in the AOT, which are distinctly different from those eliminated by solKS58 and mnb1 (Hoube, 1992).


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

date revised: 20 November 2016 

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