Conditional deletion of Hand2 reveals critical functions in neurogenesis and cell type-specific gene expression for development of neural crest-derived noradrenergic sympathetic ganglion neurons
Conditional deletion of Hand2 reveals critical functions in neurogenesis and cell type-specific gene expression for development of neural crest-derived noradrenergic sympathetic ganglion neurons
复制标题
DOI：
10.1016/j.ydbio.2008.03.036
复制
发表时间：
2008-07-15
影响因子：
2.7
通讯作者：
Howard, Marthe J.
中科院分区：
文献类型：
--
作者：
Hendershot, Tyler J.;Liu, Hongbin;Howard, Marthe J.
神经嵴衍生的结构，关键取决于表达的基本螺旋-环-螺旋DNA结合蛋白Hand 2的正常发展，包括颅面软骨和骨，心脏流出道，心脏垫，和去甲肾上腺素能交感神经节神经元。Hand 2的缺失在E9.5时是胚胎致死的，避免了对其体内功能的遗传分析。我们已经克服了这个困难，通过特定的删除Hand 2在神经嵴衍生的细胞，通过交叉我们的线floxed Hand 2小鼠与Wnt 1-Cre转基因小鼠。我们对神经嵴衍生细胞中Hand 2敲除的分析揭示了对所有表达Hand 2的神经嵴衍生结构发育的影响。在自主神经系统中，Hand 2的条件性破坏导致神经元的显著和进行性损失以及TH表达的显著损失。Hand 2通过影响祖细胞的增殖能力以及影响Phox 2a和Gata 3的表达来影响神经前体细胞库的产生，Phox 2a和Gata 3是对去甲肾上腺素能神经元的细胞自主发育重要的DNA结合蛋白。我们的数据表明，手2是一个多功能的DNA结合蛋白影响分化和细胞类型特异性基因表达的神经嵴衍生的去甲肾上腺素能交感神经节神经元。Hand 2在DNA结合蛋白的非线性交叉调节网络中具有关键功能，该网络影响细胞对分化和细胞类型特异性基因表达的自主控制。(c)2008年爱思唯尔公司All rights reserved.
Neural crest-derived structures that depend critically upon expression of the basic helix-loop-helix DNA binding protein Hand2 for normal development include craniofacial cartilage and bone, the outflow tract of the heart, cardiac cushion, and noradrenergic sympathetic ganglion neurons. Loss of Hand2 is embryonic lethal by E9.5, obviating a genetic analysis of its in-vivo function. We have overcome this difficulty by specific deletion of Hand2 in neural crest-derived cells by crossing our line of floxed Hand2 mice with Wnt1-Cre transgenic mice. Our analysis of Hand2 knock-out in neural crest-derived cells reveals effects on development in all neural crest-derived structures where Hand2 is expressed. in the autonomic nervous system, conditional disruption of Hand2 results in a significant and progressive loss of neurons as well as a significant loss of TH expression. Hand2 affects generation of the neural precursor pool of cells by affecting both the proliferative capacity of the progenitors as well as affecting expression of Phox2a and Gata3, DNA binding proteins important for the cell autonomous development of noradrenergic neurons. Our data suggest that Hand2 is a multifunctional DNA binding protein affecting differentiation and cell type-specific gene expression in neural crest-derived noradrenergic sympathetic ganglion neurons. Hand2 has a pivotal function in a non-linear cross-regulatory network of DNA binding proteins that affect cell autonomous control of differentiation and cell type-specific gene expression. (c) 2008 Elsevier Inc. All rights reserved.