Identification of novel Hoxa1 downstream targets regulating hindbrain, neural crest and inner ear development.
Identification of novel Hoxa1 downstream targets regulating hindbrain, neural crest and inner ear development.
复制标题
DOI：
10.1016/j.ydbio.2011.06.042
复制
发表时间：
2011-09-15
影响因子：
2.7
通讯作者：
Capecchi MR
中科院分区：
文献类型：
--
作者：
Makki N;Capecchi MR
Hoxgenes在胚胎形成和器官发生过程中起着至关重要的作用。在39个Hox基因中，Hoxa 1是第一个在胚胎发育过程中表达的基因，也是唯一一个与人类综合征相关的前Hox基因。Hoxa 1对于人类和小鼠的脑干、内耳和心脏的正常发育是必需的;然而，人们对它发挥功能的分子下游靶点几乎一无所知。为了深入了解这种蛋白质调控的转录网络，我们对从Hoxa 1无效和野生型胚胎的菱形节3-5区域显微切割的组织进行了微阵列分析。由于该基因的非常早期和瞬时表达，在发育的8小时时间窗期间对早期体节期胚胎进行解剖。我们的阵列产生了两个样本之间差异表达的约300个基因的列表。许多已鉴定的基因在特定的发育或细胞过程中发挥作用。一些经验证的目标调节早期神经嵴诱导和特化。有趣的是，其中三个基因，Zic 1，Hnf 1b和Foxd 3，在后脑后部下调，心脏神经嵴细胞出现，心脏流出道的图案。其他靶点是早期内耳发育所必需的，例如Pax 8和Fgfr 3，或者在调节呼吸的特定后脑神经元中表达，例如Lhx 5。这些发现使我们能够提出一个模型，其中Hoxa 1在控制胚胎发育特定方面的基因上游的遗传级联中起作用，从而深入了解人类HoxA 1综合征的可能机制。
Hoxgenes play a crucial role during embryonic patterning and organogenesis. Of the 39 Hox genes, Hoxa1 is the first to be expressed during embryogenesis and the only anterior Hox gene linked to a human syndrome. Hoxa1 is necessary for proper development of the brainstem, inner ear and heart in humans and mice; however, almost nothing is known about the molecular downstream targets through which it exerts its function. To gain insight into the transcriptional network regulated by this protein, we performed microarray analysis on tissue microdissected from the prospective rhombomere 3–5 region of Hoxa1 null and wild type embryos. Due to the very early and transient expression of this gene, dissections were performed on early somite stage embryos during an eight-hour time window of development. Our array yielded a list of around 300 genes differentially expressed between the two samples. Many of the identified genes play a role in a specific developmental or cellular process. Some of the validated targets regulate early neural crest induction and specification. Interestingly, three of these genes, Zic1, Hnf1b and Foxd3, were down-regulated in the posterior hindbrain, where cardiac neural crest cells arise, which pattern the outflow tract of the heart. Other targets are necessary for early inner ear development, e.g. Pax8 and Fgfr3 or are expressed in specific hindbrain neurons regulating respiration, e.g. Lhx5. These findings allow us to propose a model where Hoxa1 acts in a genetic cascade upstream of genes controlling specific aspects of embryonic development, thereby providing insight into possible mechanisms underlying the human HoxA1-syndrome.
登录
查看更多内容
DOI：
10.1073/pnas.0405776102
发表时间：
2005-02-01
影响因子：
11.1
作者：
Haumaitre, C;Barbacci, E;Cereghini, S
通讯作者：
Cereghini, S
影响因子：
64.8
作者：
HENRIQUE, D;ADAM, J;ISHHOROWICZ, D
通讯作者：
ISHHOROWICZ, D
影响因子：
3.5
作者：
Cepeda-Nieto, AC;Pfaff, SL;Varela-Echavarría, A
通讯作者：
Varela-Echavarría, A
影响因子：
1.2
作者：
Elms, P;Scurry, A;Arkell, R
通讯作者：
Arkell, R
影响因子：
56.9
作者：
Gray, PA;Fu, H;Ma, QF
通讯作者：
Ma, QF