RBFOX1 and RBFOX2 are dispensable in iPSCs and iPSC-derived neurons and do not contribute to neural-specific paternal UBE3A silencing.
RBFOX1 and RBFOX2 are dispensable in iPSCs and iPSC-derived neurons and do not contribute to neural-specific paternal UBE3A silencing.
复制标题
RBFOX1和RBFOX2在IPSC和IPSC衍生的神经元中是可分配的，并且不促进神经特异性的父亲UBE3A沉默。
DOI：
10.1038/srep25368
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发表时间：
2016-05-05
影响因子：
4.6
通讯作者：
Chamberlain SJ
中科院分区：
文献类型：
--
作者：
Chen PF;Hsiao JS;Sirois CL;Chamberlain SJ
Angelman综合征（AS）是一种罕见的神经发育障碍，由母体遗传的UBE3A拷贝功能丧失引起。UBE3A是一种在大多数组织中双等位表达的印迹基因，但在神经元中仅由母体等位基因表达。神经元特异性长链非编码RNA (lncRNA) UBE3A- ats的主动转录已被证明可以使父系UBE3A沉默。我们假设选择性剪接因子RBFOX2和RBFOX1可能介导了神经元的剪接变化并导致了UBE3A-ATS的转录。我们发现RBFOX2和RBFOX1在神经元中都与UBE3A-ATS转录物结合，但在SNURF/SNRPN-UBE3A区域的基因表达和/或神经元特异性加工中并不需要。然而，我们发现RBFOX2的缺失在未成熟的神经培养物中引起增殖表型，这表明RBFOX2参与了ipsc衍生的神经祖细胞的分裂与分化决策。RBFOX2的缺失也改变了一些基因的表达，这些基因在成熟神经元培养中对谷氨酸能新皮层发育和wnt -卷曲信号传导很重要。我们的数据表明，虽然RBFOX1和RBFOX2不介导UBE3A-ATS的神经元特异性加工，但这些蛋白在神经元发育中发挥重要作用，并且在功能上并非完全冗余。
Angelman Syndrome (AS) is a rare neurodevelopmental disorder caused by loss of function of the maternally inherited copy of UBE3A, an imprinted gene expressed biallelically in most tissues, but expressed exclusively from the maternal allele in neurons. Active transcription of the neuron-specific long non-coding RNA (lncRNA), UBE3A-ATS, has been shown to silence paternal UBE3A. We hypothesized that alternative splicing factors RBFOX2 and RBFOX1 might mediate splicing changes and result in the transcription of UBE3A-ATS in neurons. We found that RBFOX2 and RBFOX1 both bind to UBE3A-ATS transcript in neurons, but are not required for gene expression and/or neuron-specific processing in the SNURF/SNRPN-UBE3A region. However, we found that depletion of RBFOX2 causes a proliferation phenotype in immature neural cultures, suggesting that RBFOX2 is involved in division versus differentiation decisions in iPSC-derived neural progenitors. Absence of RBFOX2 also altered the expression of some genes that are important for glutamatergic neocortical development and Wnt-Frizzled signalling in mature neuronal cultures. Our data show that while RBFOX1 and RBFOX2 do not mediate neuron-specific processing of UBE3A-ATS, these proteins play important roles in developing neurons and are not completely functionally redundant.