Cho Ginam, Lim Youngshin, Cho Il-Taeg, Simonet Jacqueline C, Golden Jeffrey A
Department of Pathology, Brigham and Women׳s Hospital, Harvard Medical School, USA; Department of Pathology and Laboratory Medicine, Children׳s Hospital of Philadelphia, USA.
Department of Pathology, Brigham and Women׳s Hospital, Harvard Medical School, USA.
Dev Biol. 2014 Sep 1;393(1):137-48. doi: 10.1016/j.ydbio.2014.06.012. Epub 2014 Jun 23.
Mutations in the Aristaless related homeodomain transcription factor (ARX) are associated with a diverse set of X-linked mental retardation and epilepsy syndromes in humans. Although most studies have been focused on its function in the forebrain, ARX is also expressed in other regions of the developing nervous system including the floor plate (FP) of the spinal cord where its function is incompletely understood. To investigate the role of Arx in the FP, we performed gain-of-function studies in the chick using in ovo electroporation, and loss-of-function studies in Arx-deficient mice. We have found that Arx, in conjunction with FoxA2, directly induces Sonic hedgehog (Shh) expression through binding to a Shh floor plate enhancer (SFPE2). We also observed that FoxA2 induces Arx through its transcriptional activation domain whereas Nkx2.2, induced by Shh, abolishes this induction. Our data support a feedback loop model for Arx function; through interactions with FoxA2, Arx positively regulates Shh expression in the FP, and Shh signaling in turn activates Nkx2.2, which suppresses Arx expression. Furthermore, our data are evidence that Arx plays a role as a context dependent transcriptional activator, rather than a primary inducer of Shh expression, potentially explaining how mutations in ARX are associated with diverse, and often subtle, defects.
无翅相关同源域转录因子（ARX）的突变与人类多种X连锁智力障碍和癫痫综合征相关。尽管大多数研究集中在其在前脑的功能，但ARX在发育中的神经系统的其他区域也有表达，包括脊髓的底板（FP），其在该区域的功能尚未完全了解。为了研究Arx在底板中的作用，我们在鸡胚中使用卵内电穿孔进行了功能获得性研究，并在Arx缺陷小鼠中进行了功能丧失性研究。我们发现，Arx与FoxA2一起，通过与Shh底板增强子（SFPE2）结合直接诱导音猬因子（Shh）的表达。我们还观察到，FoxA2通过其转录激活域诱导Arx，而由Shh诱导的Nkx2.2则消除这种诱导作用。我们的数据支持Arx功能的反馈回路模型；通过与FoxA2相互作用，Arx正向调节底板中Shh的表达，而Shh信号反过来激活Nkx2.2，从而抑制Arx的表达。此外，我们的数据证明Arx作为一种依赖于上下文的转录激活因子发挥作用，而不是Shh表达的主要诱导因子，这可能解释了ARX中的突变如何与多样且往往细微的缺陷相关联。
