minibrain


Regulation

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).

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).


DEVELOPMENTAL BIOLOGY

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).

Embryonic

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).

Larval

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)

Adult

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).


REFERENCES

Adayev, T., et al. (2006). MNB/DYRK1A phosphorylation regulates the interactions of synaptojanin 1 with endocytic accessory proteins. Biochem. Biophys. Res. Commun. 351(4): 1060-5. PubMed Citation: 17097615

Aranda, S., et al. (2008). Sprouty2-mediated inhibition of fibroblast growth factor signaling is modulated by the protein kinase DYRK1A. Mol. Cell. Biol. 28(19): 5899-911. PubMed Citation: 18678649

Atas-Ozcan, H., Brault, V., Duchon, A. and Herault, Y. (2021). Dyrk1a from Gene Function in Development and Physiology to Dosage Correction across Life Span in Down Syndrome. Genes (Basel) 12(11). PubMed ID: 34828439

Bescond, M. and Rahmani, Z. (2005). Dual-specificity tyrosine-phosphorylated and regulated kinase 1A (DYRK1A) interacts with the phytanoyl-CoA alpha-hydroxylase associated protein 1 (PAHX-AP1), a brain specific protein. Int. J. Biochem. Cell. Biol. 37(4): 775-83. 15694837

Chen, H. and Antonarakis, S. E. (1997). Localisation of a human homologue of the Drosophila mnb and rat Dyrk genes to chromosome 21q22.2. Hum. Genet. 99 (2): 262-265.

Chen-Hwang, M. C., et al. (2002). Dynamin is a minibrain kinase/dual specificity Yak1-related kinase 1A substrate. J. Biol. Chem. 277(20): 17597-604. 11877424

Degoutin, J. L., Milton, C. C., Yu, E., Tipping, M., Bosveld, F., Yang, L., Bellaiche, Y., Veraksa, A. and Harvey, K. F. (2013). Riquiqui and Minibrain are regulators of the Hippo pathway downstream of Dachsous. Nat Cell Biol. PubMed ID: 23955303

Deng, X., et al. (2003). Mirk/dyrk1B is a Rho-induced kinase active in skeletal muscle differentiation. J. Biol. Chem. 278(42): 41347-54. 12902328

Fernandez-Martinez, J., et al. (2009). Attenuation of Notch signalling by the Down-syndrome-associated kinase DYRK1A. J Cell Sci. 122(Pt 10): 1574-83. PubMed Citation: 19383720

Fotaki, V., et al. (2002). Dyrk1A haploinsufficiency affects viability and causes developmental delay and abnormal brain morphology in mice. Mol. Cell. Biol. 22(18): 6636-47. 12192061

Guimera, J., et al. (1996). A human homologue of Drosophila minibrain (MNB) is expressed in the neuronal regions affected in Down syndrome and maps to the critical region. Hum. Mol. Genet. 5 (9): 1305-1310. PubMed Citation: 8872470

Hammerle, B., et al. (2002). Mnb/Dyrk1A is transiently expressed and asymmetrically segregated in neural progenitor cells at the transition to neurogenic divisions. Dev. Biol. 246: 259-273. 12051815

Hammerle, B., et al. (2003). Expression patterns and subcellular localization of the Down syndrome candidate protein MNB/DYRK1A suggest a role in late neuronal differentiation. Eur. J. Neurosci. 17(11): 2277-86. 12814361

Hämmerle, B., et al. (2011). Transient expression of Mnb/Dyrk1a couples cell cycle exit and differentiation of neuronal precursors by inducing p27KIP1 expression and suppressing NOTCH signaling. Development 138(12): 2543-54. PubMed Citation: 21610031

Hofbauer, A. and Campos-Ortega, J. A. (1990). Proliferation pattern and early differentiation of the optic lobes in Drosophila melanogaster. Roux's Arch. Dev. Biol. 198: 264-274

Hong, S. H., Lee, K. S., Kwak, S. J., Kim, A. K., Bai, H., Jung, M. S., Kwon, O. Y., Song, W. J., Tatar, M. and Yu, K. (2012). Minibrain/Dyrk1a regulates food intake through the Sir2-FOXO-sNPF/NPY pathway in Drosophila and mammals. PLoS Genet 8: e1002857. Pubmed: 22876196

Hoube, B. and Fischbach, K. F. (1992). Additive gene actions on the fiber number in the anterior optic tract of Drosophila melanogaster. J Neurogenet 8 (2): 115-123. PubMed Citation: 1634996

Kelly, P. A. and Rahmani, Z. (2005). DYRK1A enhances the mitogen-activated protein kinase cascade in PC12 cells by forming a complex with Ras, B-Raf, and MEK1. Mol. Biol. Cell 16(8): 3562-73. 15917294

Kim, E. J., et al. (2006). Dyrk1A phosphorylates alpha-synuclein and enhances intracellular inclusion formation. J. Biol. Chem. 281(44): 33250-7. PubMed Citation: 16959772

Kim, O. H., Cho, H. J., Han, E., Hong, T. I., Ariyasiri, K., Choi, J. H., Hwang, K. S., Jeong, Y. M., Yang, S. Y., Yu, K., Park, D. S., Oh, H. W., Davis, E. E., Schwartz, C. E., Lee, J. S., Kim, H. G. and Kim, C. H. (2017). Zebrafish knockout of Down syndrome gene, DYRK1A, shows social impairments relevant to autism. Mol Autism 8: 50. PubMed ID: 29021890

Kinstrie, R., Lochhead, P. A., Sibbet, G., Morrice, N. and Cleghon, V. (2006). dDYRK2 and Minibrain interact with the chromatin remodelling factors SNR1 and TRX. Biochem J. 398(1): 45-54. PubMed Citation: 16671894

Kurabayashi, N. and Sanada, K. (2013). Increased dosage of DYRK1A and DSCR1 delays neuronal differentiation in neocortical progenitor cells. Genes Dev 27: 2708-2721. PubMed ID: 24352425

Laguna, A., et al. (2008). The protein kinase DYRK1A regulates caspase-9-mediated apoptosis during retina development. Dev. Cell 15(6): 841-53. PubMed Citation: 19081073

Lee, K. S., Kwon, O. Y., Lee, J. H., Kwon, K., Min, K. J., Jung, S. A., Kim, A. K., You, K. H., Tatar, M. and Yu, K. (2008). Drosophila short neuropeptide F signalling regulates growth by ERK-mediated insulin signalling. Nat Cell Biol 10: 468-475. Pubmed: 18344986

Lochhead, P. A., et al. (2003). dDYRK2: a novel dual-specificity tyrosine-phosphorylation-regulated kinase in Drosophila. Biochem J. 374(Pt 2): 381-91. 12786602

Lochhead, P. A., et al. (2005). Activation-loop autophosphorylation is mediated by a novel transitional intermediate form of DYRKs. Cell 121(6): 925-36. 15960979

Marco Antonio, D. S. and Hartfelder, K. (2016). Toward an understanding of divergent compound eye development in drones and workers of the honeybee (Apis mellifera L.): A correlative analysis of morphology and gene expression. J Exp Zool B Mol Dev Evol [Epub ahead of print]. PubMed ID: 27658924

Miyata, Y. and Nishida, E. (2021). Protein quality control of DYRK family protein kinases by the Hsp90-Cdc37 molecular chaperone. Biochim Biophys Acta Mol Cell Res 1868(10): 119081. PubMed ID: 34147560

Murakami, N., et al. (2006). Phosphorylation of amphiphysin I by minibrain kinase/dual-specificity tyrosine phosphorylation-regulated kinase, a kinase implicated in Down syndrome. J. Biol. Chem. 281(33): 23712-24. PubMed Citation: 16733250

Pang, K. M., et al. (2004). The minibrain kinase homolog, mbk-2, is required for spindle positioning and asymmetric cell division in early C. elegans embryos. Dev. Biol. 265(1): 127-39. 14697358

Raich, W. B., et al. (2003). Characterization of Caenorhabditis elegans homologs of the Down syndrome candidate gene DYRK1A. Genetics 163(2): 571-80. 12618396

Selleck, S. B. and Steller, H. (1991). The influence of retinal innervation on neurogenesis in the first optic ganglion of Drosophila. Neuron 6: 83-99. PubMed Citation: 1898850

Shaikh, M. N., Gutierrez-Avino, F., Colonques, J., Ceron, J., Hammerle, B. and Tejedor, F. J. (2016). Minibrain drives the Dacapo dependent cell cycle exit of neurons in the Drosophila brain by promoting asense and prospero expression. Development 143(17): 3195-205. PubMed ID: 27510975

Shindoh, N., et al. (1997). Cloning of a human homolog of the Drosophila minibrain/rat Dyrk gene from "the Down syndrome critical region" of chromosome 21. Biochem. Biophys. Res. Commun. 225 (1): 92-99. PubMed Citation: 8769099

Sitz, J. H., et al. (2008). The Down syndrome candidate dual-specificity tyrosine phosphorylation-regulated kinase 1A phosphorylates the neurodegeneration-related septin 4. Neuroscience 157(3): 596-605. PubMed Citation: 18938227

Smith, D. J., et al. (1997). Functional screening of 2 Mb of human chromosome 21q22.2 in transgenic mice implicates minibrain in learning defects associated with Down syndrome Nat. Genet. 16 (1): 28-36. PubMed Citation: 9140392

Song, W. J., et al. (1996). Isolation of human and murine homologues of the Drosophila minibrain gene: human homologue maps to 21q22.2 in the Down syndrome "critical region". Genomics 38 (3): 331-339. PubMed Citation: 8975710

Tejedor, F., et al. (1995). minibrain: a new protein kinase family involved in postembryonic neurogenesis in Drosophila. Neuron 14: 287-301. PubMed Citation: 7857639

Thomazeau, A., Lassalle, O., Iafrati, J., Souchet, B., Guedj, F., Janel, N., Chavis, P., Delabar, J. and Manzoni, O. J. (2014). Prefrontal deficits in a murine model overexpressing the down syndrome candidate gene dyrk1a. J Neurosci 34: 1138-1147. PubMed ID: 24453307

Zou, M., et al. (2003). Serine/threonine kinase Mirk/Dyrk1B is an inhibitor of epithelial cell migration and is negatively regulated by the Met adaptor Ran-binding protein. J. Biol. Chem. 278(49): 49573-8114500717


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

date revised: 22 March 2022 

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