Seattle Children's Research Institute, Seattle, WA 98101.
Proc Natl Acad Sci U S A. 2014 Apr 29;111(17):E1777-86. doi: 10.1073/pnas.1315024111. Epub 2014 Apr 14.
Model organism studies have demonstrated that cell fate specification decisions play an important role in normal brain development. Their role in human neurodevelopmental disorders, however, is poorly understood, with very few examples described. The cerebellum is an excellent system to study mechanisms of cell fate specification. Although signals from the isthmic organizer are known to specify cerebellar territory along the anterior-posterior axis of the neural tube, the mechanisms establishing the cerebellar anlage along the dorsal-ventral axis are unknown. Here we show that the gene encoding pancreatic transcription factor PTF1A, which is inactivated in human patients with cerebellar agenesis, is required to segregate the cerebellum from more ventral extracerebellar fates. Using genetic fate mapping in mice, we show that in the absence of Ptf1a, cells originating in the cerebellar ventricular zone initiate a more ventral brainstem expression program, including LIM homeobox transcription factor 1 beta and T-cell leukemia homeobox 3. Misspecified cells exit the cerebellar anlage and contribute to the adjacent brainstem or die, leading to cerebellar agenesis in Ptf1a mutants. Our data identify Ptf1a as the first gene involved in the segregation of the cerebellum from the more ventral brainstem. Further, we propose that cerebellar agenesis represents a new, dorsal-to-ventral, cell fate misspecification phenotype in humans.
模式生物研究表明，细胞命运特化决定在正常大脑发育中起着重要作用。然而，它们在人类神经发育障碍中的作用还知之甚少，仅有少数例子被描述。小脑是研究细胞命运特化机制的绝佳系统。尽管已知来自视丘组织者的信号沿神经管的前后轴特化小脑区域，但沿背腹轴建立小脑原基的机制尚不清楚。在这里，我们发现编码胰腺转录因子 PTF1A 的基因在小脑发育不全的人类患者中失活，对于将小脑与更腹侧的外小脑命运区分开来是必需的。通过在小鼠中的遗传命运映射，我们发现，在 Ptf1a 缺失的情况下，起源于小脑室区的细胞启动更腹侧脑干表达程序，包括 LIM 同源盒转录因子 1β和 T 细胞白血病同源盒 3。错误指定的细胞离开小脑原基并贡献给相邻的脑干或死亡，导致 Ptf1a 突变体中的小脑发育不全。我们的数据将 Ptf1a 鉴定为第一个参与从小脑与更腹侧脑干区分的基因。此外，我们提出小脑发育不全代表人类中一种新的、背腹侧的细胞命运特化异常表型。
