Two subunits of the<i>Drosophila</i>mediator complex act together to control cell affinity

Janody, Florence; Martirosyan, Zara; Benlali, Aude; Treisman, Jessica E.

doi:10.1242/dev.00607

Cited by 90 publications

(101 citation statements)

References 87 publications

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“…These observations suggest that the mot͞med12 gene plays a regulatory role in vertebrate neuronal development. Consistent with this notion, it is interesting to mention that Caenorhabditis elegans (22)(23)(24)(25) and Drosophila (26,27) mutants in med12 also display specific phenotypes, and human polymorphisms in med12͞hopa correlate with distinct brain diseases such as schizophrenia and hypothyroidism (28).…”

Section: Discussionmentioning

confidence: 79%

A subunit of the mediator complex regulates vertebrate neuronal development

Wang

Yang

Uno

et al. 2006

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

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The unique profiles of gene expression dictate distinct cellular identity. How these profiles are established during development is not clear. Here we report that the mutant motionless (mot), identified in a genetic screen for mutations that affect neuronal development in zebrafish, displays deficits of monoaminergic neurons and cranial sensory ganglia, whereas expression of the panneuronal marker Hu is largely unperturbed; GABAergic and subsets of cranial motor neurons do not appear to be deficient. Positional cloning reveals that mot encodes Med12, a component of the evolutionarily conserved Mediator complex, whose in vivo function is not well understood in vertebrates. mot͞med12 transcripts are enriched in the embryonic brain and appear distinct from two other Mediator components Med17 and Med21. Delivery of human med12 RNA into zebrafish restores normality to the mot mutant and, strikingly, leads to premature neuronal differentiation and an increased production of monoaminergic neuronal subtypes in WT. Further investigation reveals that mot͞med12 is necessary to regulate, and when overexpressed is capable of increasing, the expression of distinct neuronal determination genes, including zash1a and lim1, and serves as an in vivo cofactor for Sox9 in this process. Together, our analyses reveal a regulatory role of Mot͞ Med12 in vertebrate neuronal development. D uring vertebrate development, pluripotent stem cells respond to spatially localized signals that regulate their cell cycle exit and subsequent differentiation into specialized cell types. The central nervous system contains a large number of different cell types and has been an organ of interest for studying progenitor cell commitment͞differentiation and the generation of cellular diversity (1, 2). In addition to spatial control, temporal regulation of neuronal development has been appreciated but is much less understood in the vertebrate nervous system (3, 4). It is widely accepted that progenitor cells need to establish unique profiles of gene expression that dictate their final destiny. Intracellular pathways underlying the establishment of precise gene expression patterns in the developing nervous system are not well understood.We have undertaken a genetic approach to characterize genes and pathways that control vertebrate neuronal development by using zebrafish as a model system (5-8). Here, we describe the molecular characterization of the motionless (mot) mutant isolated from our genetic screen. The mot mutant embryos have defects in movement and neuronal and cardiovascular development (9). Current analyses reveal that they have normal brain patterning and do not suffer a global deficit of neurons as evidenced by largely unperturbed expression of the pan-neuronal marker Hu. However, the mot mutant exhibits deficits in neuronal subtypes that include monoaminergic (MA) neurons [forebrain dopaminergic and serotonergic (5HT) neurons, hindbrain noradrenergic (NA) and 5HT neurons, and neural-crest derived sympathetic neurons] and cranial sensory gangli...

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Section: Discussionmentioning

confidence: 79%

A subunit of the mediator complex regulates vertebrate neuronal development

Wang

Yang

Uno

et al. 2006

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

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“…Increasing evidence has shown that subunits in other topological positions participate in development regulation in a complex and precise manner. For instance, two subunits in the CDK module of the Drosophila Mediator, MED12 (TRAP230) and MED13 (TRAP240), physically interact with each other controlling cell affinity (Janody et al, 2003). In Arabidopsis, three subunits in the head module of the Mediator complex, MED17, MED18 and MED20, are involved in development by regulating the expression of micro-RNA biosynthesis genes .…”

Section: Discussionmentioning

confidence: 99%

The Arabidopsis Mediator subunit MED16 regulates iron homeostasis by associating with EIN3/EIL1 through subunit MED25

et al. 2014

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These authors contributed equally to this work. SUMMARYIron is an essential micronutrient for plants and animals, and plants are a major source of iron for humans. Therefore, understanding the regulation of iron homeostasis in plants is critical. We identified a T-DNA insertion mutant, yellow and sensitive to iron-deficiency 1 (yid1), that was hypersensitive to iron deficiency, containing a reduced amount of iron. YID1 encodes the Arabidopsis Mediator complex subunit MED16. We demonstrated that YID1/MED16 interacted with another subunit, MED25. MED25 played an important role in regulation of iron homeostasis by interacting with EIN3 and EIL1, two transcription factors in ethylene signaling associated with regulation of iron homeostasis. We found that the transcriptome in yid1 and med25 mutants was significantly affected by iron deficiency. In particular, the transcription levels of FIT, IRT1 and FRO2 were reduced in the yid1 and med25 mutants under iron-deficient conditions. The finding that YID1/MED16 and MED25 positively regulate iron homeostasis in Arabidopsis increases our understanding of the complex transcriptional regulation of iron homeostasis in plants.

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“…17 mRNA expression of MED13L in human has been detected in fetal brain and heart, and adult tissues including skeletal muscle, brain (especially, cerebellum), heart and aorta, kidney and peripheral blood leukocytes. 2,3 Animal studies imply a specific role for MED13, similar in size and B50% identical to MED13L, in regulating transcription of Wnt and Notch target genes, and Hh signal transduction, [18][19][20] which are involved in neural crest induction. 21 Neural crest cell migration has an important role in the development of the heart, the nervous system and the facial mesenchyme, which could explain the syndromic signs of MED13L haploinsufficiency and the clinical overlap with DiGeorge Figure 2 Copy number variants of MED13L in our patients.…”

Section: Discussionmentioning

confidence: 99%

“…The third patient is a girl born 5 days preterm with a history of transient but marked fetal hydrops during pregnancy (weeks [16][17][18][19][20][21][22][23][24][25]. Her birth weight was 2200 g (o3rd centile) and the length was 47 cm (3rd centile).…”

Section: Patientmentioning

confidence: 99%

Dosage changes of MED13L further delineate its role in congenital heart defects and intellectual disability

Asadollahi

Oneda

Sheth³

et al. 2013

Eur J Hum Genet

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A chromosomal balanced translocation disrupting the MED13L (Mediator complex subunit13-like) gene, encoding a subunit of the Mediator complex, was previously associated with transposition of the great arteries (TGA) and intellectual disability (ID), and led to the identification of missense mutations in three patients with isolated TGA. Recently, a homozygous missense mutation in MED13L was found in two siblings with non-syndromic ID from a consanguineous family. Here, we describe for the first time, three patients with copy number changes affecting MED13L and delineate a recognizable MED13L haploinsufficiency syndrome. Using high resolution molecular karyotyping, we identified two intragenic de novo frameshift deletions, likely resulting in haploinsufficiency, in two patients with a similar phenotype of hypotonia, moderate ID, conotruncal heart defect and facial anomalies. In both, Sanger sequencing of MED13L did not reveal any pathogenic mutation and exome sequencing in one patient showed no evidence for a non-allelic second hit. A further patient with hypotonia, learning difficulties and perimembranous VSD showed a 1 Mb de novo triplication in 12q24.2, including MED13L and MAP1LC3B2. Our findings show that MED13L haploinsufficiency in contrast to the previously observed missense mutations cause a distinct syndromic phenotype. Additionally, a MED13L copy number gain results in a milder phenotype. The clinical features suggesting a neurocristopathy may be explained by animal model studies indicating involvement of the Mediator complex subunit 13 in neural crest induction.

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Two subunits of theDrosophilamediator complex act together to control cell affinity

Cited by 90 publications

References 87 publications

A subunit of the mediator complex regulates vertebrate neuronal development

A subunit of the mediator complex regulates vertebrate neuronal development

The Arabidopsis Mediator subunit MED16 regulates iron homeostasis by associating with EIN3/EIL1 through subunit MED25

Dosage changes of MED13L further delineate its role in congenital heart defects and intellectual disability

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