Bradley Cara K, Takano Elena A, Hall Mark A, Göthert Joachim R, Harvey Alan R, Begley C Glenn, van Eekelen J Anke M
Telethon Institute for Child Health Research and Centre for Child Health Research at the University of Western Australia, Subiaco WA 6008, Australia.
Eur J Neurosci. 2006 Apr;23(7):1677-89. doi: 10.1111/j.1460-9568.2006.04712.x.
Abstract The basic helix-loop-helix (bHLH) transcription factor Scl displays tissue-restricted expression and is critical for the establishment of the haematopoietic system; loss of Scl results in embryonic death due to absolute anaemia. Scl is also expressed in neurons of the mouse diencephalon, mesencephalon and metencephalon; however, its requirement in those sites remains to be determined. Here we report conditional deletion of Scl in neuronal precursor cells using the Cre/LoxP system. Neuronal-Scl deleted mice died prematurely, were growth retarded and exhibited an altered motor phenotype characterized by hyperactivity and circling. Moreover, ablation of Scl in the nervous system affected brain morphology with abnormal neuronal development in brain regions known to express Scl under normal circumstances; there was an almost complete absence of Scl-null neurons in the hindbrain and partial loss of Scl-null neurons in the thalamus and midbrain from early neurogenesis onwards. Our results demonstrate a crucial role for Scl in the development of Scl-expressing neurons, including gamma-aminobutyric acid (GABA)ergic interneurons. Our study represents one of the first demonstrations of functional overlap of a single bHLH protein that regulates neural and haematopoietic cell development. This finding underlines Scl's critical function in cell fate determination of mesodermal as well as neuroectodermal tissues.
摘要 基本螺旋-环-螺旋（bHLH）转录因子Scl表现出组织限制性表达，对造血系统的建立至关重要；Scl缺失会因绝对贫血导致胚胎死亡。Scl在小鼠间脑、中脑和后脑的神经元中也有表达；然而，其在这些部位的作用仍有待确定。在此，我们报告利用Cre/LoxP系统在神经元前体细胞中条件性删除Scl。神经元Scl缺失的小鼠过早死亡，生长发育迟缓，并表现出以多动和转圈为特征的运动表型改变。此外，神经系统中Scl的缺失影响脑形态，在正常情况下已知表达Scl的脑区出现神经元发育异常；从早期神经发生开始，后脑几乎完全没有Scl缺失的神经元，丘脑和中脑有部分Scl缺失的神经元丢失。我们的结果证明Scl在表达Scl的神经元（包括γ-氨基丁酸（GABA）能中间神经元）的发育中起关键作用。我们的研究是首次证明单一bHLH蛋白在调节神经和造血细胞发育方面存在功能重叠的研究之一。这一发现强调了Scl在中胚层以及神经外胚层组织细胞命运决定中的关键作用。
