Atrx Deletion in Neurons Leads to Sexually Dimorphic Dysregulation of miR-137 and Spatial Learning and Memory Deficits.,Cell Reports

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Atrx Deletion in Neurons Leads to Sexually Dimorphic Dysregulation of miR-137 and Spatial Learning and Memory Deficits.
Cell Reports ( IF 7.5 ) Pub Date : 2020-06-30 , DOI: 10.1016/j.celrep.2020.107838
Renee J Tamming ₁ , Vanessa Dumeaux ₂ , Yan Jiang ₃ , Sarfraz Shafiq ₄ , Luana Langlois ₅ , Jacob Ellegood ₆ , Lily R Qiu ₇ , Jason P Lerch ₈ , Nathalie G Bérubé ₉

Affiliation

Children's Health Research Institute, London, ON, Canada; Lawson Health Research Institute, London, ON, Canada; Department of Biochemistry, Western University, London, ON, Canada.
Department of Paediatrics, Western University, London, ON, Canada; PERFORM Centre, Concordia University, Montreal, QC, Canada.
Children's Health Research Institute, London, ON, Canada; Lawson Health Research Institute, London, ON, Canada.
Children's Health Research Institute, London, ON, Canada; Department of Paediatrics, Western University, London, ON, Canada; Department of Anatomy & Cell Biology, Western University, London, ON, Canada.
Children's Health Research Institute, London, ON, Canada; Lawson Health Research Institute, London, ON, Canada; Department of Anatomy & Cell Biology, Western University, London, ON, Canada.
Mouse Imaging Centre, The Hospital for Sick Children, Toronto, ON, Canada.
Mouse Imaging Centre, The Hospital for Sick Children, Toronto, ON, Canada; Wellcome Centre for Integrative Neuroimaging, The University of Oxford, Oxford, UK.
Mouse Imaging Centre, The Hospital for Sick Children, Toronto, ON, Canada; Department of Medical Biophysics, The University of Toronto, Toronto, ON, Canada; Wellcome Centre for Integrative Neuroimaging, The University of Oxford, Oxford, UK.
Children's Health Research Institute, London, ON, Canada; Lawson Health Research Institute, London, ON, Canada; Department of Paediatrics, Western University, London, ON, Canada; Department of Anatomy & Cell Biology, Western University, London, ON, Canada; Department of Oncology, Western University, London, ON, Canada.

ATRX gene mutations have been identified in syndromic and non-syndromic intellectual disabilities in humans. ATRX is known to maintain genomic stability in neuroprogenitor cells, but its function in differentiated neurons and memory processes remains largely unresolved. Here, we show that the deletion of neuronal Atrx in mice leads to distinct hippocampal structural defects, fewer presynaptic vesicles, and an enlarged postsynaptic area at CA1 apical dendrite-axon junctions. We identify male-specific impairments in long-term contextual memory and in synaptic gene expression, linked to altered miR-137 levels. We show that ATRX directly binds to the miR-137 locus and that the enrichment of the suppressive histone mark H3K27me3 is significantly reduced upon the loss of ATRX. We conclude that the ablation of ATRX in excitatory forebrain neurons leads to sexually dimorphic effects on miR-137 expression and on spatial memory, identifying a potential therapeutic target for neurological defects caused by ATRX dysfunction.

中文翻译：

神经元中的Atrx缺失会导致miR-137的性二态失调以及空间学习和记忆障碍。

在人类的有症状和无症状的智力障碍中已经鉴定出ATRX基因突变。已知ATRX可以在神经祖细胞中维持基因组稳定性，但是在分化的神经元和记忆过程中其功能仍未解决。在这里，我们表明，小鼠神经元Atrx的缺失导致明显的海马结构缺陷，较少的突触前囊泡和CA1根尖突-轴突交界处的突触后区域扩大。我们确定长期上下文记忆和突触基因表达，与改变的miR-137水平相关的男性特异性损伤。我们证明ATRX直接与miR-137结合以及在丢失ATRX后显着降低了抑制性组蛋白标记H3K27me3的富集。我们得出的结论是，兴奋性前脑神经元中ATRX的消融导致miR-137表达和空间记忆发生性二态性作用，从而确定了ATRX功能障碍引起的神经功能缺损的潜在治疗靶标。

更新日期：2020-06-30

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