Geng Xin, Acosta Sandra, Lagutin Oleg, Gil Hyea Jin, Oliver Guillermo
Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA.
Center for Vascular and Developmental Biology, Feinberg Cardiovascular Research Institute, Northwestern University, Chicago, IL 60611, USA.
Development. 2016 Dec 1;143(23):4462-4473. doi: 10.1242/dev.132142. Epub 2016 Oct 21.
Holoprosencephaly (HPE) is defined as the incomplete separation of the two cerebral hemispheres. The pathology of HPE is variable and, based on the severity of the defect, HPE is divided into alobar, semilobar, and lobar. Using a novel hypomorphic Six3 allele, we demonstrate in mice that variability in Six3 dosage results in different HPE phenotypes. Furthermore, we show that whereas the semilobar phenotype results from severe downregulation of Shh expression in the rostral diencephalon ventral midline, the alobar phenotype is caused by downregulation of Foxg1 expression in the anterior neural ectoderm. Consistent with these results, in vivo activation of the Shh signaling pathway rescued the semilobar phenotype but not the alobar phenotype. Our findings show that variations in Six3 dosage result in different forms of HPE.
全前脑畸形（HPE）被定义为两个大脑半球未完全分离。HPE的病理学表现多样，根据缺陷的严重程度，HPE可分为无叶型、半叶型和叶型。利用一种新的Six3低表达等位基因，我们在小鼠中证明Six3剂量的变化会导致不同的HPE表型。此外，我们发现半叶型表型是由端脑腹侧中线中Shh表达的严重下调引起的，而无叶型表型是由前神经外胚层中Foxg1表达的下调导致的。与这些结果一致，Shh信号通路的体内激活挽救了半叶型表型，但未挽救无叶型表型。我们的研究结果表明，Six3剂量的变化会导致不同形式的HPE。
