Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0004134 (ataxia)
 15,886 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Mutations of leukaemia associated AF9/MLLT3 are implicated in neurodevelopmental diseases such as epilepsia and ataxia. This study shows for the first time, that murine Af9 is transcribed in various CNS structures including the subventricular zone (SVZ) of the cerebral cortex, hippocampus, cerebellar cortex, septum and various thalamic structures, the choroid plexus, and the midbrain/hindbrain boundary. Expression of Af9 in the SVZ overlaps with Svet1, Cux2, and partially with Tbr2, confining its activity to the neurogenic compartment of the SVZ. In contrast to Svet1 and Cux2 expression, Af9 transcription is not limited to upper layer neurons but is found in the entire cortical plate. As part of an extensive network of interacting proteins involved in epigenetic DNA modification, we could show overlapping expression of Af9 with Af4/Aff1 and Fmr2/Aff2, two genes that are also related to neurodevelopmental diseases, as well as with the highly homologous Enl.
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PMID:Expression of Leukaemia associated transcription factor Af9/Mllt3 in the cerebral cortex of the mouse. 1900 Jul 83

Mutations of leukemia-associated AF9/MLLT3 are implicated in neurodevelopmental diseases, such as epilepsy and ataxia, but little is known about how AF9 influences brain development and function. Analyses of mouse mutants revealed that during cortical development, AF9 is involved in the maintenance of TBR2-positive progenitors (intermediate precursor cells, IPCs) in the subventricular zone and prevents premature cell cycle exit of IPCs. Furthermore, in postmitotic neurons of the developing cortical plate, AF9 is implicated in the formation of the six-layered cerebral cortex by suppressing a TBR1-positive cell fate mainly in upper layer neurons. We show that the molecular mechanism of TBR1 suppression is based on the interaction of AF9 with DOT1L, a protein that mediates transcriptional control through methylation of histone H3 lysine 79 (H3K79). AF9 associates with the transcriptional start site of Tbr1, mediates H3K79 dimethylation of the Tbr1 gene, and interferes with the presence of RNA polymerase II at the Tbr1 transcriptional start site. AF9 expression favors cytoplasmic localization of TBR1 and its association with mitochondria. Increased expression of TBR1 in Af9 mutants is associated with increased levels of TBR1-regulated expression of NMDAR subunit Nr1. Thus, this study identified AF9 as a developmental active epigenetic modifier during the generation of cortical projection neurons.
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PMID:Af9/Mllt3 interferes with Tbr1 expression through epigenetic modification of histone H3K79 during development of the cerebral cortex. 2034 16