DYRK1A-dosage imbalance perturbs NRSF/REST levels, deregulating pluripotency and embryonic stem cell fate in Down syndrome
DYRK1A-dosage imbalance perturbs NRSF/REST levels, deregulating pluripotency and embryonic stem cell fate in Down syndrome
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DOI：
10.1016/j.ajhg.2008.08.012
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发表时间：
2008-09-12
影响因子：
9.8
通讯作者：
Nizetic, Dean
中科院分区：
文献类型：
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作者：
Canzonetta, Claudia;Mulligan, Claire;Nizetic, Dean
唐氏综合症(DS)是导致精神发育迟滞的最常见原因。许多神经表型在DS个体和DS小鼠模型之间是相同的；然而，共同的潜在分子致病机制仍然不清楚。利用DS的跨染色体模型，我们发现Nrsf/REST(多能性和神经元分化的关键调节因子)的表达减少30%-60%是一种从未分化的胚胎干细胞到成人脑的21三体持续存在的变化，并可在几种DS模型中重现。使用部分三体ES细胞，我们将这种效应映射到HSA21的一个包含DYRK1A的三基因片段。我们独立地确定了与人类基因组中控制REST表达的最显著eQTL相同的基因座。我们表明，特异性沉默DYRK1A的第三个副本拯救了REST水平，我们证明了REST表达的改变对DYRK1A表达或激酶活性的抑制，以及在转基因Dyrk1A小鼠中的表达。我们发现未分化的21三体ES细胞表现出DYRK1A剂量敏感的一些多能性调节因子水平的降低，导致驱动早期内胚层和中胚层分化的转录因子的过早表达，部分重叠了最近报道的REST+/-的下游效应。它们产生的类胚体具有原始内胚层前体标记GATA4的高水平，以及神经外胚层前体隔室的强烈减少。我们的结果表明，DYRK1A介导的REST的解除调控是21三体的一个非常早期的病理结果，有可能干扰所有胚胎谱系的发育，需要对其在DS病理中的贡献和治疗方法的新理论进行更深入的研究。
Down syndrome (DS) is the most common cause of mental retardation. Many neural phenotypes are shared between DS individuals and DS mouse models; however, the common underlying molecular pathogenetic mechanisms remain unclear. Using a transchromosomic model of DS, we show that a 30%-60% reduced expression of Nrsf/Rest (a key regulator of pluripotency and neuronal differentiation) is an alteration that persists in trisomy 21 from undifferentiated embryonic stem (ES) cells to adult brain and is reproducible across several DS models. Using partially trisomic ES cells, we map this effect to a three-gene segment of HSA21, containing DYRK1A. We independently identify the same locus as the most significant eQTL controlling REST expression in the human genome. We show that specifically silencing the third copy of DYRK1A rescues Rest levels, and we demonstrate altered Rest expression in response to inhibition of DYRK1A expression or kinase activity, and in a transgenic Dyrk1A mouse. We reveal that undifferentiated trisomy 21 ES cells show DYRK1A-dosesensitive reductions in levels of some pluripotency regulators, causing premature expression of transcription factors driving early endodermal and mesodermal differentiation, partially overlapping recently reported downstream effects of Rest +/-. They produce embryoid bodies with elevated levels of the primitive endoderm progenitor marker Gata4 and a strongly reduced neuroectodermal progenitor compartment. Our results suggest that DYRK1A-mediated deregulation of REST is a very early pathological consequence of trisomy 21 with potential to disturb the development of all embryonic lineages, warranting closer research into its contribution to DS pathology and new rationales for therapeutic approaches.