Minibrain/Dyrk1a Regulates Food Intake through the Sir2-FOXO-sNPF/NPY Pathway in Drosophila and Mammals

Hong, Seung-Hyun; Lee, Kyu-Sun; Kwak, Sangshin; Kim, Ae-Kyeong; Bai, Hua; Jung, Min-Su; Kwon, O‐Yu; Song, Woo-Joo; Tatar, Marc; Yu, Kweon

doi:10.1371/journal.pgen.1002857

Cited by 116 publications

(117 citation statements)

References 57 publications

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“…37 Finally, in the Dyrk1a mouse and the mbn fly AKT-mediated insulin signaling pathway suppresses FOXO-mediated neuropeptide Y expression, which results in decreasing food intake. 38 We propose that the IUGR, postnatal growth retardation, microcephaly, seizures, behavior abnormalities, ataxia, eye defects, brain findings (gliosis, cortex atrophy, and white matter hypomyelination), minor skeletal anomalies, feeding, and GI issues are consistent with the gene dysregulation of multiple DYRK1A interactors, as these findings are all present in both Dykr1a ( ± ) mice and our cohort.…”

Section: Discussionsupporting

confidence: 64%

DYRK1A haploinsufficiency causes a new recognizable syndrome with microcephaly, intellectual disability, speech impairment, and distinct facies

et al. 2015

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Dual-specificity tyrosine-(Y)-phosphorylation-regulated kinase 1 A (DYRK1A ) is a highly conserved gene located in the Down syndrome critical region. It has an important role in early development and regulation of neuronal proliferation. Microdeletions of chromosome 21q22.12q22.3 that include DYRK1A (21q22.13) are rare and only a few pathogenic single-nucleotide variants (SNVs) in the DYRK1A gene have been described, so as of yet, the landscape of DYRK1A disruptions and their associated phenotype has not been fully explored. We have identified 14 individuals with de novo heterozygous variants of DYRK1A; five with microdeletions, three with small insertions or deletions (INDELs) and six with deleterious SNVs. The analysis of our cohort and comparison with published cases reveals that phenotypes are consistent among individuals with the 21q22.12q22.3 microdeletion and those with translocation, SNVs, or INDELs within DYRK1A. All individuals shared congenital microcephaly at birth, intellectual disability, developmental delay, severe speech impairment, short stature, and distinct facial features. The severity of the microcephaly varied from − 2 SD to − 5 SD. Seizures, structural brain abnormalities, eye defects, ataxia/broadbased gait, intrauterine growth restriction, minor skeletal abnormalities, and feeding difficulties were present in two-thirds of all affected individuals. Our study demonstrates that haploinsufficiency of DYRK1A results in a new recognizable syndrome, which should be considered in individuals with Angelman syndrome-like features and distinct facial features. Our report represents the largest cohort of individuals with DYRK1A disruptions to date, and is the first attempt to define consistent genotype-phenotype correlations among subjects with 21q22.13 microdeletions and DYRK1A SNVs or small INDELs.

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Section: Discussionsupporting

confidence: 64%

DYRK1A haploinsufficiency causes a new recognizable syndrome with microcephaly, intellectual disability, speech impairment, and distinct facies

et al. 2015

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“…To identify the tissue origins of the reduction in adult brain size, we studied the larval and pupal brains from the wild-type and mnb d419 animals (mnb d419 is a null allele; ref. 34). The volumes of the larval and pupal brains in the mnb d419 mutants were significantly smaller than controls (Fig.…”

Section: Significancementioning

confidence: 85%

Minibrain and Wings apart control organ growth and tissue patterning through down-regulation of Capicua

Liu

Paul

Trieu

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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The transcriptional repressor Capicua (Cic) controls tissue patterning and restricts organ growth, and has been recently implicated in several cancers. Cic has emerged as a primary sensor of signaling downstream of the receptor tyrosine kinase (RTK)/extracellular signal-regulated kinase (ERK) pathway, but how Cic activity is regulated in different cellular contexts remains poorly understood. We found that the kinase Minibrain (Mnb, ortholog of mammalian DYRK1A), acting through the adaptor protein Wings apart (Wap), physically interacts with and phosphorylates the Cic protein. Mnb and Wap inhibit Cic function by limiting its transcriptional repressor activity. Down-regulation of Cic by Mnb/Wap is necessary for promoting the growth of multiple organs, including the wings, eyes, and the brain, and for proper tissue patterning in the wing. We have thus uncovered a previously unknown mechanism of down-regulation of Cic activity by Mnb and Wap, which operates independently from the ERK-mediated control of Cic. Therefore, Cic functions as an integrator of upstream signals that are essential for tissue patterning and organ growth. Finally, because DYRK1A and CIC exhibit, respectively, prooncogenic vs. tumor suppressor activities in human oligodendroglioma, our results raise the possibility that DYRK1A may also down-regulate CIC in human cells.

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“…Dyrk1A is part of a positive feedback loop that regulates neuropeptide Y levels and consequently food intake. 51 Although many of the five principal clinical features found in patients with DYRK1A defects are also typically present in a number of other monogenic (eg Rett, Christianson and FOXG1 syndromes) and chromosomal disorders (eg 1p36 deletion syndrome), patients with DYRK1A-associated ID can be distinguished based on other commonly observed manifestations. Often these patients also present with thin upper lip vermilion border (86.7%), deep-set eyes with somewhat full/hooded upper lids (85.7%), stereotypies (80%), hyperopia/myopia (77.8%), clumsy or incoordinated movement (75%), and micrognathia (71.4%).…”

Section: Resultsmentioning

confidence: 99%

Ten new cases further delineate the syndromic intellectual disability phenotype caused by mutations in DYRK1A

et al. 2015

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The dual-specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A) gene, located on chromosome 21q22.13 within the Down syndrome critical region, has been implicated in syndromic intellectual disability associated with Down syndrome and autism. DYRK1A has a critical role in brain growth and development primarily by regulating cell proliferation, neurogenesis, neuronal plasticity and survival. Several patients have been reported with chromosome 21 aberrations such as partial monosomy, involving multiple genes including DYRK1A. In addition, seven other individuals have been described with chromosomal rearrangements, intragenic deletions or truncating mutations that disrupt specifically DYRK1A. Most of these patients have microcephaly and all have significant intellectual disability. In the present study, we report 10 unrelated individuals with DYRK1A-associated intellectual disability (ID) who display a recurrent pattern of clinical manifestations including primary or acquired microcephaly, ID ranging from mild to severe, speech delay or absence, seizures, autism, motor delay, deep-set eyes, poor feeding and poor weight gain. We identified unique truncating and non-synonymous mutations (three nonsense, four frameshift and two missense) in DYRK1A in nine patients and a large chromosomal deletion that encompassed DYRK1A in one patient. On the basis of increasing identification of mutations in DYRK1A, we suggest that this gene be considered potentially causative in patients presenting with ID, primary or acquired microcephaly, feeding problems and absent or delayed speech with or without seizures.

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Minibrain/Dyrk1a Regulates Food Intake through the Sir2-FOXO-sNPF/NPY Pathway in Drosophila and Mammals

Cited by 116 publications

References 57 publications

DYRK1A haploinsufficiency causes a new recognizable syndrome with microcephaly, intellectual disability, speech impairment, and distinct facies

DYRK1A haploinsufficiency causes a new recognizable syndrome with microcephaly, intellectual disability, speech impairment, and distinct facies

Minibrain and Wings apart control organ growth and tissue patterning through down-regulation of Capicua

Ten new cases further delineate the syndromic intellectual disability phenotype caused by mutations in DYRK1A

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