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  1. 与发育相关的基因 张咸宁 zhangxianning@zju.edu.cn Tel:13105819271; 88208367 Office: A705, Research Building 2013/09

  2. 出生缺陷(Birth defect):即先天性疾病 • Malformation畸形is a primary morphologic defect of an organ or body part resulting from an intrinsically abnormal developmental process (e.g., cleft lip, polydactyly). • Dysplasia发育异常is a primary defect involving abnormal organization of cells into tissue (e.g., vascular malformation). • Sequence序列征is a primary defect with its secondary structural changes (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) • Syndrome综合征is a pattern of multiple primary malformations with a single etiology (e.g., trisomy 13 syndrome). • Deformation变形is alteration of the form, shape, or position of a normally formed body part by mechanical forces. It usually occurs in the fetal period, not in embryogenesis. It is a secondary alteration. It can be extrinsic, as in oligohydramnios羊水过少 (reduced amniotic fluid), or intrinsic, as in congenital myotonic dystrophy. • Disruption畸化is a morphological defect of an organ, part of an organ, or a larger region of the body resulting from the extrinsic breakdown of, or interference with, an originally normal developmental process. It is a secondary malformation (e.g., secondary limb defect resulting from a vascular event).

  3. Developmental Gene Families • Model animals: Drosophila melanogaster, frog, mouse, chick, zebra-fish… • Transcription factors can switch genes on and off by activating or repressing gene expression. • Fundamental embryological processes: induction (the process in which extracellular signals give rise to a change from one cell fate to another in a particular group of cells), segmentation, migration, differentiation, and PCD (apoptosis). • These processes are mediated by growth factors, cell receptors, and chemicals (morphogens).

  4. Transcription factors • These gene regulatory proteins have a transcriptional activation domain and a DNA-binding domain. • 4 types of DNA-binding domain: helix-turn-helix, zinc finger, leucine zipper, helix-loop-helix.

  5. Early Patterning • Induction of the mesoderm-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) and WNTs (wingless) are involved in maintenance, and BMPs (bone morphogenetic proteins) are involved in patterning the mesoderm. • The WNT pathway has two main branches: β-catenin-dependent (canonical) , independent of β-catenin. • E.g., Mutated WNT10A in man results in a form of ectodermal dysplasia (odonto-onychodermal dysplasia).

  6. The TGF-β (transforming growth factor-β) Superfamily in Development and Disease • 33 members of this cytokine family. • 2 groups: (1) the BMPs, (2) the TGF-βs, activins, nodal, and myostatin, acting through various SMAD proteins. • Regulation of the cell cycle, cell migration, cell size, gastrulation and axis specification, and metabolic processes. • In relation to health and disease, there are consequences for immunity, cancer, heart disease, diabetes, and Marfan syndrome.

  7. Fig. 6b

  8. 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’-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 region in a rostral(嘴的) direction and has a key role in the process leading to the defining of somite 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.

  9. The Sonic Hedgehog-Patched GLI Pathway • The Sonic hedgehog gene (SHH) induces cell proliferation in a tissue-specific distribution and is expressed in the notochord, 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.

  10. Homeobox (HOX) 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 has 8 Hox genes arranged in a single cluster. • Humans, as in most vertebrates, 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-genital syndrome.

  11. Homeobox(同源〔异型〕框)refers to nucleic acid. Homeodomain(同源〔异型〕域)refers to protein. 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. Define Hox, homeobox The term homeobox is reserved for the nucleic acid sequences that encode homeodomains. Since they are highly conserved, and can be detected by low-stringency hybridization across species.

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

  13. 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).

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

  15. SRY-type HMG (high-mobility group) Box (SOX) Genes • The SOX genes are transcription regulators and are expressed in specific tissues during embryogenesis. • 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.

  16. 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 syndrome.

  17. Zinc Finger Genes • The zinc finger refers to a finger-like loop projection 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.

  18. Signal Transduction ('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.

  19. The RET Proto-oncogene • Gain-of-function mutations, whether inherited or acquired, are found in a high proportion of thyroid cancers. • 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.

  20. FGF Receptors

  21. The Pharyngeal Arches(咽弓) • The pharyngeal (or branchial) arches correspond to the gill system of lower vertebrates and appear in the fourth and fifth weeks of development. • Five (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.

  22. Acknowledge(PPT特别鸣谢!) • UCLA David Geffen School of Medicine • www.medsch.ucla.edu/ANGEL/ • Prof. RobertisE(UCLA), et al.