Hox基因在中枢神经系统中作用的研究进展

同源异型盒基因(homeobox genes,Hox)在进化上是保守的,在调节胚胎发育,尤其在脊椎动物前–后轴(antero-posterior axis)的发育及肢体发育中起着重要作用。最近研究表明,Hox基因通过与之相关的辅助因子调节中枢神经系统(central nervous system,CNS)以及神经环路的发育。该文主要对Hox基因调控中枢神经系统发育的作用及机制进行综述。     

Hox基因及其进化机制的研究进展

Hox基因是生物体内一类重要的发育调控基因家族.Hox基因高度保守,通常成簇存在,编码一类转录因子,在个体胚胎发育中起着重要的调控作用.近期研究表明,基因复制、基因序列变异及选择压力对Hox基因簇的产生和进化有重要作用,同时调节元件和协同进化对Hox基因的进化也有重要影响.     

基因倍增和脊椎动物起源

有机体基因复制导致基因复杂性增加及其和脊椎动物起源的关系已经成为进化生物学研究的热点。20世纪70年代由Ohno提出后经Holland等修正的原始脊索动物经两轮基因组复制产生脊椎动物的假设目前已被广泛接受。脊椎动物起源和进化过程中发生过两轮基因组复制的主要证据有三点：（1）据估计脊椎动物基因组内编码基因数目大约相当于果蝇、海鞘等无脊椎动物的4倍;原口动物如果蝇和后口动物如头索动物文昌鱼的基因组大都只有单拷贝的基因,而脊椎动物的基因组则通常有4个同属于一个家族的基因。（2）无脊椎动物如节肢动物、海胆和头索动物文昌鱼都只有一个Hox基因簇,而脊椎动物除鱼类外,有7个具有Hox基因簇,其余都具有4个Hox基因簇。（3）基因作图证明,不但在鱼类和哺乳动物染色体广大片段上基因顺序相似,而且有证据显示哺乳动物基因组不同染色体之间存在相似性。据认为第一次基因倍增发生在脊椎动物与头索动物分开之后,第二次基因倍增发生在有颌类脊椎动物和无颌类脊椎动物分开以后。但是,基因是逐个发生倍增,还是通过基因组内某些DNA片段抑或整个基因组的加倍而实现的,目前还颇有争议。     

PcG蛋白复合体对Hox基因调节的研究

PcG蛋白广泛参与到生长、发育、增殖、分化以及肿瘤发生等重要过程.而目前为止对PcG蛋白的靶基因研究最透彻的就是Hox家族. Hox基因存在于一个高度保守的基因簇内,在调控维持正常发育及肿瘤发生中有重要作用.一般认为,PcG蛋白复合物对Hox基因进行以组蛋白表观修饰为主的沉默作用,指导Hox基因适时适地发挥功能. 同时,这个过程还需要DNA连接蛋白、ncRNA等分子的辅助.本文对Hox基因和PcG蛋白的组成和功能进行介绍,并重点归纳总结了对二者关系的经典和最新认识.     

果蝇心脏发育研究三十年进展

果蝇(Drosophila melanogaster)作为最早用于研究心脏发育基因调控的模式生物,已经走过三十年的历程。果蝇心脏发育过程经历了胚胎期、幼虫期和成虫期三大阶段。在胚胎早期, Tinman、Dorsocross和Pannier等基因是关键的调控因子。Tinman参与最早的心脏前体细胞分化和心脏细胞形成,而Dorsocross和Pannier则影响心脏前体细胞的定向分化和心脏管腔的形成。进入胚胎晚期和幼虫期,果蝇的心管经历进一步的发展和重塑,该过程主要受到转录因子Hand、Mef2以及Hox基因家族的调控。在成虫期, Hox基因家族和Tinman依旧发挥重要作用。虽然果蝇心脏与脊椎动物成熟心脏存在形态上的差异,但两者心脏的早期发育过程以及调控基因和信号通路都有保守性。本文综述了果蝇心脏发育基因调控研究的三十年进展以及利用果蝇模型研究人类心脏相关疾病的潜在希望。     

海胆Runx基因的研究进展

海胆Runx(Runt box)基因是Runx基因家族的成员之一,在海胆的胚胎发育、细胞的增殖和分化过程中起重要的作用.海胆Runx基因表达的缺失或下调,将会影响其它相关基因的表达,进而影响胚胎的正常发育.综述了海胆Runx基因的研究进展.     

天然免疫系统新成员Akirin的研究进展

天然免疫系统是多细胞动物抵御细菌感染的第一道防线。Akirin是新近发现于果蝇中的天然免疫系统新成员,它在果蝇免疫缺陷(Imd)通路中发挥重要作用。Akirin同源基因广泛存在于从低等多细胞生物到高等脊椎动物中,进化上高度保守。已有的研究表明:Akirin在果蝇Imd通路和脊椎动物TLR通路下游,与NF-κB家族转录因子形成复合物,参与调控免疫相关靶基因的转录,是天然免疫调控机制中不可或缺的转录因子,其过表达或缺失直接影响动物对细菌的防御能力。近年来,Akirin在相关信号通路中的功能研究取得重大进展。该文对Akirin的结构、参与天然免疫的分子调控机制以及基因进化等方面进行综述。     

基于全基因组的龟鳖目Hox基因序列特征及进化分析

为对Hox基因在龟鳖目物种中进行系统地序列比较分析和进化研究，文章对目前具有染色体水平的龟鳖目基因组进行了Hox基因的鉴定,序列特征、进化和转录组分析。研究结果表明龟鳖物种的Hox基因簇是高度保守的。非重复序列的缺失导致鳖科HoxB9—HoxB13基因间区相对龟科短了10 kb。大量Hox基因编码区发生了鳖科或龟科特异的序列替换、插入和缺失。胸部骨骼发育相关的Hox基因在鳖科祖先发生了快速进化和受到正选择。Hox基因的表达具有组织、时期特异性,主要在胚胎时期的顶端外胚层嵴、背甲嵴和性腺表达。研究为龟鳖目Hox基因不同胚胎时期的多组学及表达调控分析提供了靶标,也为进一步厘清龟鳖物种演化创新提供了参考。     

爬行动物MHC基因研究进展

主要组织相容性复合体(MHC)是有颌脊椎动物中发现的编码免疫球蛋白受体的高度多态的基因群,因其在免疫系统中的重要作用而备受关注。脊椎动物不同支系间MHC的结构和演化差异较大。尽管MHC基因特征在哺乳类、鸟类、两栖类和鱼类中已被较好地描述,但对爬行动物MHC的了解仍较少。鉴于爬行动物对于理解MHC基因的演化占据很重要的系统发育位置,研究其MHC具有重要意义。本文就近年来爬行动物MHC的分子结构、多态性维持机制、功能和主要应用的研究现状进行了系统地回顾和总结,并展望了其研究前景。     

同源异形盒基因是造血细胞分化的一种潜在性调节因子

同源异形盒(homeobox)基因是最先在果蝇中发现的一段长约180碱基对的DNA片段,这些基因影响果蝇的早期发育,并能编码出高度保守的DNA结合区域。近来,在一些脊椎动物中亦分离到同源异形盒基因,这些基因在脊椎动物中的胚胎期表达形式类似于果蝇。因此,一些脊椎动物同源异形盒基因可能控制早期发育,并且可能在成年分化过程中起重要作用。T、B淋巴细胞等血液细胞是从造血干细胞分化来的。实验结果表明,同源异形盒基因可能参与造血细胞分化的控制。     

A conserved role for the nodal signaling pathway in the establishment of dorso-ventral and left-right axes in deuterostomes

Nodal factors play crucial roles during embryogenesis of chordates. They have been implicated in a number of developmental processes, including mesoderm and endoderm formation and patterning of the embryo along the anterior-posterior and left-right axes. We have analyzed the function of the Nodal signaling pathway during the embryogenesis of the sea urchin, a non-chordate organism. We found that Nodal signaling plays a central role in axis specification in the sea urchin, but surprisingly, its first main role appears to be in ectoderm patterning and not in specification of the endoderm and mesoderm germ layers as in vertebrates. Starting at the early blastula stage, sea urchin nodal is expressed in the presumptive oral ectoderm where it controls the formation of the oral-aboral axis. A second conserved role for nodal signaling during vertebrate evolution is its involvement in the establishment of left-right asymmetries. Sea urchin larvae exhibit profound left-right asymmetry with the formation of the adult rudiment occurring only on the left side. We found that a nodal/lefty/pitx2 gene cassette regulates left-right asymmetry in the sea urchin but that intriguingly, the expression of these genes is reversed compared to vertebrates. We have shown that Nodal signals emitted from the right ectoderm of the larva regulate the asymmetrical morphogenesis of the coelomic pouches by inhibiting rudiment formation on the right side of the larva. This result shows that the mechanisms responsible for patterning the left-right axis are conserved in echinoderms and that this role for nodal is conserved among the deuterostomes. We will discuss the implications regarding the reference axes of the sea urchin and the ancestral function of the nodal gene in the last section of this review.     

Unusual gene order and organization of the sea urchin hox cluster

While the highly consistent gene order and axial colinear patterns of expression seem to be a feature of vertebrate hox gene clusters, this pattern may be less well conserved across the rest of the bilaterians. We report the first deuterostome instance of an intact hox cluster with a unique gene order where the paralog groups are not expressed in a sequential manner. The finished sequence from BAC clones from the genome of the sea urchin, Strongylocentrotus purpuratus, reveals a gene order wherein the anterior genes (Hox1, Hox2 and Hox3) lie nearest the posterior genes in the cluster such that the most 3' gene is Hox5. (The gene order is 5'-Hox1, 2, 3, 11/13c, 11/13b, 11/13a, 9/10, 8, 7, 6, 5-3'.) The finished sequence result is corroborated by restriction mapping evidence and BAC-end scaffold analyses. Comparisons with a putative ancestral deuterostome Hox gene cluster suggest that the rearrangements leading to the sea urchin gene order were many and complex.     

Hox genes in a pentameral animal

There is renewed interest in how the different body plans of extant phyla are related. This question has traditionally been addressed by comparisons between vertebrates and Drosophila. Fortunately, there is now increasing emphasis on animals representing other phyla. Pentamerally symmetric echinoderms are a bilaterian metazoan phylum whose members exhibit secondarily derived radial symmetry. Precisely how their radially symmetric body plan originated from a bilaterally symmetric ancestor is unknown, however, two recent papers address this subject. Peterson et al. propose a hypothesis on evolution of the anteroposterior axis in echinoderms, and Arenas-Mena et al. examine expression of five posterior Hox genes during development of the adult sea urchin.     

Sea urchin Hox genes: insights into the ancestral Hox cluster

We describe the Hox cluster in the radially symmetric sea urchin and compare our findings to what is known from clusters in bilaterally symmetric animals. Several Hox genes from the direct-developing sea urchin Heliocidaris erythrogramma are described. CHEF gel analysis shows that the Hox genes are clustered on a < or = 300 kilobase (kb) fragment of DNA, and only a single cluster is present, as in lower chordates and other nonvertebrate metazoans. Phylogenetic analyses of sea urchin, amphioxus, Drosophila, and selected vertebrate Hox genes confirm that the H. erythrogramma genes, and others previously cloned from other sea urchins, belong to anterior, central, and posterior groups. Despite their radial body plan and lack of cephalization, echinoderms retain at least one of the anterior group Hox genes, an orthologue of Hox3. The structure of the echinoderm Hox cluster suggests that the ancestral deuterostome had a Hox cluster more similar to the current chordate cluster than was expected Sea urchins have at least three Abd-B type genes, suggesting that Abd-B expansion began before the radiation of deuterostomes.      

Genomic analysis of Hox clusters in the sea lamprey Petromyzon marinus

The sea lamprey Petromyzon marinus is among the most primitive of extant vertebrates. We are interested in the organization of its Hox gene clusters, because, as a close relative of the gnathostomes, this information would help to infer Hox cluster organization at the base of the gnathostome radiation. We have partially mapped the P. marinus Hox clusters using phage, cosmid, and P1 artificial chromosome libraries. Complete homeobox sequences were obtained for the 22 Hox genes recovered in the genomic library screens and analyzed for cognate group identity. We estimate that the clusters are somewhat larger than those of mammals (roughly 140 kbp vs. 105 kbp) but much smaller than the single Hox cluster of the cephalochordate amphioxus (at more than 260 kb). We never obtained more than three genes from any single cognate group from the genomic library screens, although it is unlikely that our screen was exhaustive, and therefore conclude that P. marinus has a total of either three or four Hox clusters. We also identify four highly conserved non-coding sequence motifs shared with higher vertebrates in a genomic comparison of Hox 10 genes.     

Unexpectedly large number of conserved noncoding regions within the ancestral chordate Hox cluster

The single amphioxus Hox cluster contains 15 genes and may well resemble the ancestral chordate Hox cluster. We have sequenced the Hox genomic complement of the European amphioxus Branchiostoma lanceolatum and compared it to the American species, Branchiostoma floridae, by phylogenetic footprinting to gain insights into the evolution of Hox gene regulation in chordates. We found that Hox intergenic regions are largely conserved between the two amphioxus species, especially in the case of genes located at the 3' of the cluster, a trend previously observed in vertebrates. We further compared the amphioxus Hox cluster with the human HoxA, HoxB, HoxC, and HoxD clusters, finding several conserved noncoding regions, both in intergenic and intronic regions. This suggests that the regulation of Hox genes is highly conserved across chordates, consistent with the similar Hox expression patterns in vertebrates and amphioxus.