与发育相关的基因和出生缺陷 张咸宁 Tel ： ; Office: C303, Teaching Building 2015/09

出生缺陷（ Birth defect ）：即先天性疾病 Malformation 畸形： A recognizable pattern of dysmorphic features having a single cause, either genetic or environmental (e.g., cleft lip 唇裂, polydactyly 多指趾 ). 单因素（遗传或环境因素）引起的畸形 Sequence 序列征： A recognizable pattern of dysmorphic features due to a number of different causes (e.g., Pierre Robin sequence, a disorder in which a primary defect in mandibular 下颌骨 development produces a small jaw, secondary glossoptosis 舌后坠, and a cleft palate 腭裂 ) 多个不同因素引起的畸 形 Dysplasia 发育异常： A congenital abnormality due to abnormal development at the tissue level of organization (dyshistogenesis 组织发生障 碍 )(e.g., vascular malformation 血管畸形 ). Syndrome 综合征： A characteristic pattern of anomalies, presumed to be causally related (e.g., trisomy 13). 特定疾病的病征和症状的总合 Deformation 变形： A recognizable pattern of dysmorphic features caused by extrinsic 外在的 factors that affect the fetus in utero. It usually occurs in the fetal period, not in embryogenesis 胚胎发生. (e.g., oligohydramnios 羊水过少 ) 子宫中因外部因素影响胎儿而导致的一种畸形 Disruption 畸化 : A birth defect caused by destruction of tissue; may be caused by vascular occlusion, a teratogen, or rupture of the amniotic sac with entrapment (e.g., secondary limb defect resulting from a vascular event). 组织破坏引起的出生缺陷；可能由血管闭塞、致畸剂或羊毛囊破裂引起

Developmental Gene Families Model animals 模式动物 : Drosophila melanogaster, frog, mouse, chick, zebra-fish… Transcription factors 转录因子 can switch genes on and off by activating or repressing gene expression. Fundamental embryological processes: induction 诱导 (the process in which extracellular signals 胞 外信号 give rise to a change from one cell fate 细胞 结局 to another in a particular group of cells), segmentation 分节, migration 迁移, differentiation 分化, and PCD (apoptosis 细胞凋亡 ). These processes are mediated by growth factors 生 长因子, cell receptors 细胞受体, and chemicals (morphogens 形态发生素 ).

Transcription factors 转录因子 These gene regulatory proteins 调控蛋白 have a transcriptional activation domain 转录激活功能域 and a DNA-binding domain DNA 结合域. 4 types of DNA-binding domain: helix- turn-helix 螺旋 - 转角 - 螺旋, zinc finger 锌 指, leucine zipper 亮氨酸拉链, helix-loop- helix 螺旋 - 环 - 螺旋.

1.Early Patterning 早期图式发育 Induction of the mesoderm 中胚层的诱导 -the initiation, maintenance, and subsequent patterning of this layer- involves several key families of signaling factors. The Nodal family is involved in initiation, FGFs (fibroblast growth factors 成纤维细胞生长因子 ) and WNTs (wingless) are involved in maintenance, and BMPs (bone morphogenetic proteins 骨形态发生蛋白 ) are involved in patterning the mesoderm. The WNT pathway has two main branches: β-catenin- dependent (canonical 标准的 ), independent of β- catenin. E.g., Mutated WNT10A in man results in a form of ectodermal dysplasia 外胚层发育不良症 (odonto- onychodermal dysplasia).

2.The TGF-β (transforming growth factor-β ) Superfamily 超家族 in Development and Disease 33 members of this cytokine family 细胞因子家族. 2 groups: (1) the BMPs, (2) the TGF-βs, activins, nodal, and myostatin 筒箭毒碱, acting through various SMAD proteins. Regulation of the cell cycle, cell migration, cell size, gastrulation 原肠胚形成 and axis 枢椎 specification, and metabolic processes. In relation to health and disease, there are consequences for immunity, cancer, heart disease, diabetes, and Marfan syndrome.

A summary of biological responses to TGF family signaling. The range of processes that come under the influence of this super family is very broad.

3.Somatogenesis （体质发生） and the Axial Skeleton （中轴骨骼） Wnt and FGF signals play vital roles in the specification of the presomitic mesoderm 前体节中胚层. The key pathway here is notch-delta signaling and the ‘oscillation clock 振荡时钟 ’-a precise, temporally defined wave of cycling gene expression (c-hairy in the chick, lunatic fringe and hes genes in the mouse) that sweeps from the tail-bud 尾芽 region in a rostral 嘴的 direction and has a key role in the process leading to the defining of somite 体节 boundaries. E.g., presenile dementia (presenilin-1), which is dominantly inherited, and spondylocostal dysostosis 脊椎 肋骨发育不全 (delta-like-3, mesoderm posterior-2, lunatic fringe, and hairy enhancer of split-7), which is recessively inherited.

Somatogenesis and Notch-Delta pathway. T-box genes have a role in PSM specification, whereas the segmentation clock depends on oscillation, or cycling, genes that are important in somite boundary formation where genes of the Notch-Delta pathway establish rostro-caudal polarity. HOX genes have a global function in establishing somite identity along the entire rostro-caudal axis.

4.The Sonic Hedgehog-Patched GLI Pathway The Sonic hedgehog gene (SHH) induces cell proliferation 增殖 in a tissue-specific distribution and is expressed in the notochord 脊索, the brain, and the zone of polarizing activity of developing limbs. The key intracellular targets are the GLI family of transcription factors. Mutations in, or deletions of, SHH (7q36) cause holoprosencephaly 前脑无裂畸形 ; Mutations in PTCH (9q22) result in Gorlin syndrome; Mutations in GLI3 (7p13) cause Pallister-Hall and Grieg syndromes.

The Sonic hedgehog (Shh)-Patched (Ptch)-Gli pathway and connection with disease. Different elements in the pathway act as activators (arrows) or inhibitors (bars). The Shh protein is initially cleaved to an active N-terminal form, which is then modified by the addition of cholesterol. The normal action of Ptch is to inhibit Smo, but when Ptch is bound by Shh this inhibition is removed and the downstream signaling proceeds. CREBBP, cAMP response element- binding binding protein.

5. Homeobox (HOX) 同源框 Genes Proteins from homeobox-containing (or HOX) genes are important transcription factors that activate and repress batteries of downstream genes. At least 35 downstream targets are known. Drosophila 果蝇 has 8 Hox genes arranged in a single cluster. Humans, as in most vertebrates 脊椎动物, there are 4 homeobox gene clusters containing a total of 39 HOX genes. E.g., Mutations in HOXA13 cause a rare condition known as the hand-foot-genitalsyndrome 手 - 足 - 外生 殖器综合征.

Define Hox, homeobox The homeodomain is a 60 AA helix-turn-helix DNA-binding domain that is very conserved during evolution. It fits into the major groove of the DNA. The term homeobox is reserved for the nucleic acid sequences that encode homeodomains. Since they are highly conserved, and can be detected by low-stringencyhybridization 低严谨杂 交 across species. Homeobox （同源〔异型〕框） refers to nucleic acid. Homeodomain （ 同源〔异型〕域） refers to protein.

Homeotic genes specify body segment identity in Drosophila. Lewis predicted Hox genes would be duplicated. Edward B. Lewis

A ： Drosophila has eight Hox genes in a single cluster whereas there are 39 HOX genes in humans, arranged in four clusters located on chromosomes 7p, 17q, 12q, and 2q for the A, B, C, and D clusters, respectively. B ： Expression patterns of Hox and HOX genes along the rostro-caudal axis in invertebrates and vertebrates, respectively. In vertebrates the clusters are paralogous and appear to compensate for one another.

Vertebrates have 4 Hox complexes, with about 10 genes each. They display colinearity （共线性） : a)Spatial （空间） colinearity: the more anteriorly （前部） expressed genes are in one end, the more posterior ones at the other end of the gene complex. b)Temporal （时间） colinearity: genes on one end of the complex are expressed first, those on the other (posterior 。后 部 ) end are turned on last. c)Anterior Hox genes are activated sequentially by retinoic acid. Hox genes can be aligned in 13 groups of paralogues 种内同源基 因 that were duplicated twice.

6. Paired-Box (PAX) Genes The paired-box is a highly conserved 高度 保守 DNA sequence that encodes a 130- amino-acid DNA-binding transcription regulator domain. 9 PAX genes have been identified in mice and humans.

7.SRY-type HMG (high-mobility 高泳 动 group) Box (SOX) Genes The SOX genes are transcription regulators and are expressed in specific tissues during embryogenesis 胚胎发生. E.g., SOX1, SOX2, and SOX3 are expressed in the developing mouse nervous system. Mutations in SOX10 on chromosome 22 cause a rare form of Waardenburg syndrome.

8. T-Box (TBX) Genes This gene, which is also known as Brachyury 鼠短尾突变体表型, encodes a transcription factor that contains both activator and repressor domains. E.g., Loss-of-function mutations in TBX3 cause the ulnar 尺骨 -mammary 乳房 syndrome.

9. Zinc Finger Genes The zinc finger refers to a finger-like loop projection 突出物 consisting of a series of four amino acids that form a complex with a zinc ion. Genes that contain a zinc finger motif act as transcription factors through binding of the zinc finger to DNA.

10.Signal Transduction 信号转导 ('Signaling') Genes Signal transduction is the process whereby extracellular growth factors regulate cell division and differentiation by a complex pathway of genetically determined intermediate steps.

（ 1 ） The RET Proto-oncogene Gain-of-function mutations, whether inherited or acquired, are found in a high proportion of thyroid cancers （多发性内分泌腺瘤 2 型 /MEN 2 ）. Loss-of-function mutations in RET have been identified in ~50% of familial cases of Hirschsprung disease, in which there is failure of migration of ganglionic cells to the submucosal and myenteric plexuses of the large bowel.

（ 2 ） FGF Receptors

A young child with achondroplasia 软骨 发育不全

11.The Pharyngeal Arches 咽弓 The pharyngeal (or branchial) arches correspond to the gill system 鳃系 of lower vertebrates and appear in the fourth and fifth weeks of development. 5 (segmented) pharyngeal arches in humans arise lateral to the structures of the head and each comprises cells from the three germ layers and the neural crest.