ALFY-Controlled DVL3 Autophagy Regulates Wnt Signaling, Determining Human Brain Size.
ALFY-Controlled DVL3 Autophagy Regulates Wnt Signaling, Determining Human Brain Size.
复制标题
DOI：
10.1371/journal.pgen.1005919
复制
发表时间：
2016-03
期刊：
影响因子：
4.5
通讯作者：
Birk OS
中科院分区：
文献类型：
--
作者：
Kadir R;Harel T;Markus B;Perez Y;Bakhrat A;Cohen I;Volodarsky M;Feintsein-Linial M;Chervinski E;Zlotogora J;Sivan S;Birnbaum RY;Abdu U;Shalev S;Birk OS
原发性小头畸形是一种先天性的神经发育障碍，表现为头围和脑容量减小，由于神经发生过程中神经元干细胞层在对称和不对称细胞分裂之间过早过渡，导致发育中的大脑皮层神经元减少。我们现在通过连锁分析和全外显子组测序表明，编码自噬支架蛋白的ALFY的显性突变导致人类原发性小头畸形。我们证明了这种突变在果蝇中的显性效应：携带人类突变等位基因的转基因果蝇显示出小的脑容量，再现了这种疾病的表型。此外，人类突变体ALFY的眼特异性表达导致粗糙的眼表型。在分子方面，我们证明ALFY通常通过自噬依赖性去除DVL3聚集体而不是Dvl1或Dvl2来减弱典型的Wnt信号通路。因此，ALFY通过去除Dvl3聚集体对Wnt信号的自噬衰减决定了人脑的大小。人类进化的一个重要事件就是从灵长类动物到人类的转变过程中脑容量的显著增加。决定人脑更大尺寸的分子途径尚不完全清楚。遗传性原发性小头畸形是一种神经发育障碍，婴儿出生时头围小，脑容量减少，伴有智力残疾，它为确定人类大脑大小的胚胎分子途径提供了见解。先前的研究表明，人类小头症可能是由影响细胞分裂过程的基因突变引起的，如细胞周期调节、DNA复制、初级纤毛形成、中心粒和中心体复制。我们现在展示了一种新的决定人类大脑大小的分子途径：人类原发性小头畸形可能是由编码自噬支架蛋白的基因ALFY突变引起的。事实上，过表达人类ALFY突变形式的转基因果蝇概括了人类小头症的疾病表型。我们展示了ALFY调节细胞分裂和分化的分子途径：我们证明ALFY通常控制DVL3聚集物的去除，并通过它调节Wnt信号通路，这是胚胎发生的主要分子途径。因此，由alfy介导的DVL3聚集去除控制的Wnt信号决定了人脑大小和人类小头畸形。
Primary microcephaly is a congenital neurodevelopmental disorder of reduced head circumference and brain volume, with fewer neurons in the cortex of the developing brain due to premature transition between symmetrical and asymmetrical cellular division of the neuronal stem cell layer during neurogenesis. We now show through linkage analysis and whole exome sequencing, that a dominant mutation in ALFY, encoding an autophagy scaffold protein, causes human primary microcephaly. We demonstrate the dominant effect of the mutation in drosophila: transgenic flies harboring the human mutant allele display small brain volume, recapitulating the disease phenotype. Moreover, eye-specific expression of human mutant ALFY causes rough eye phenotype. In molecular terms, we demonstrate that normally ALFY attenuates the canonical Wnt signaling pathway via autophagy-dependent removal specifically of aggregates of DVL3 and not of Dvl1 or Dvl2. Thus, autophagic attenuation of Wnt signaling through removal of Dvl3 aggregates by ALFY acts in determining human brain size. One of the major events in human evolution is the significant increase in brain volume in the transition from primates to humans. The molecular pathways determining the larger size of the human brain are not fully understood. Hereditary primary microcephaly, a neurodevelopmental disorder in which infants are born with small head circumference and reduced brain volume with intellectual disability, offers insights to the embryonic molecular pathways determining human brain size. Previous studies have shown that human microcephaly can be caused by mutations in genes affecting cell division processes, such as cell cycle regulation, DNA replication, primary cilia formation and centriole and centrosome duplication. We now show a novel molecular pathway determining human brain size: human primary microcephaly can be caused by a mutation in ALFY, a gene that encodes an autophagy scaffold protein. In fact, transgenic flies over expressing the mutant form of human ALFY recapitulate the human disease phenotype of microcephaly. We show the molecular pathway through which ALFY regulates cell division and differentiation: we demonstrate that ALFY normally controls removal of aggregate of DVL3, and through this regulates Wnt signaling, a major molecular pathway in embryogenesis. Thus, Wnt signaling, controlled by ALFY-mediated aggregate removal of DVL3, determines human brain size and human microcephaly.