浙江大学医学院：Molecular Regulation of Development. Growth factor signaling, Hox genes and the body plan

Molecular regulation of Development Growth factor signaling, Hox genes and the body plan 张咸宁 zhangxianning@zju.edu.cn Tel:13105819271;88208367 Office: A705, Research Building 2012/09

Molecular Regulation of Development. Growth factor signaling, Hox genes and the body plan 张咸宁 zhangxianning@zju.edu.cn Tel：13105819271; 88208367 Office: A705, Research Building 2012/09

出生缺陷( Birth defect):即先天性疾病 Malformation is a primary morphologic defect of an organ or body part resulting from an intrinsically abnormal developmental process(e. g. cleft lip, polydactyly) Dysplasia is a primary defect involving abnormal organization of cells into tissue(e. g, vascular malformation). Sequence is a primary defect with its secondary structural changes(e. g Pierre robin sequence, a disorderin which a primary defect in mandibular development produces a smalljaw, secondary glossoptosis, and a cleft palate Syndrome is a pattern of multiple primary malformations with a single etiology(e.g, trisomy 13 syndrome). Deformation is alteration of the form, shape, or position of a normall 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(reduced amniotic fluid), or intrinsic, as in congenital myotonic dystrophy. Disruption is a morphologicaldefect 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)

出生缺陷（Birth defect）：即先天性疾病 • Malformation is a primary morphologic defect of an organ or body part resulting from an intrinsically abnormal developmental process (e.g., cleft lip, polydactyly). • Dysplasia is a primary defect involving abnormal organization of cells into tissue (e.g., vascular malformation). • Sequence is a primary defect with its secondary structural changes (e.g., Pierre Robin sequence, a disorder in which a primary defect in mandibular development produces a small jaw, secondary glossoptosis, and a cleft palate) • Syndrome is a pattern of multiple primary malformations with a single etiology (e.g., trisomy 13 syndrome). • Deformation 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 (reduced amniotic fluid), or intrinsic, as in congenital myotonic dystrophy. • Disruption 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)

Three questions 1. How is dorsal-ventral(D-V背腹)cll differentiation regulated by morphogen 形态发 生素) gradients 梯度)∵BMP(骨形态发生 蛋白) signal transduction 2. Hox is the the antero- posterior(A-P前后) pattern regulated by hox genes? Colinearity(共线性) Activation by retinoic acid(视黄酸) Retinoid receptors. 3. How have conserved(保守) gene networks affected Evolution and development? Evo-Devo

Three questions: 1. How is dorsal-ventral (D-V背腹 ) cell differentiation regulated by morphogen（形态发 生素）gradients（梯度）. BMP（骨形态发生 蛋白） signal transduction. 2. Hox is the the antero-posterior (A-P前后 ) pattern regulated by Hox genes? - Colinearity（共线性） - Activation by retinoic acid（视黄酸）. Retinoid receptors. 3. How have conserved（保守）gene networks affected Evolution and Development? Evo-Devo

1. During development groups of inducing cells called organizing centers secrete graded growth factor signals. The concentration gradient of a"morphogen"can induce multiple cell differentiation choices inductive signal OOOOO ○○○o○o●●○o○○○ cells directed to new developmental pathway Figure 21-12. Molecular Biology of the Cell, 4th Edition

1. During development groups of inducing cells called organizing centers secrete graded growth factor signals. The concentration gradient of a “morphogen” can induce multiple cell differentiation choices. Fig. 1

ectoderm (epidermis ectoderm (neural plate notochord D-V patterning can blastopore lip be studied in the somites lateral plate yolk frog embryo. endoderm (B) brain spinal cord blastopore (C) Figure 21-71 part 2 of 2. Molecular Biology of the Cell, 4th Edition. Fig 2

D-V patterning can be studied in the frog embryo. Fig. 2

The best example of a morphogen is the gradient of BMP signaling that controls D-V tissue differentiation neural crest (ectoderm) somite(mesoderm) neural tube (ectoderm) notochord(mesoderm) gut cavity (lined G by endoderm) tail bud head lateral plate mesoderm endoderm and yolk eye epidermis (ectoderm) Figure 21-70. Molecular Biology of the Cell, 4th Edition

The best example of a morphogen is the gradient of BMP signaling that controls D-V tissue differentiation. Fig. 3a

Mesoderm(中胚层) cell differentiation is determined by a morphogen gradient of BMP. ventral dorsal Lateral plate Somite Notochord BMPs are members of the tGFB superfamily Fig 3b

Lateral plate Somite Notochord BMP signaling Mesoderm（中胚层） cell differentiation is determined by a morphogen gradient of BMP. BMPs are members of the TGFβ superfamily. ventral dorsal Fig. 3b

Genes specifically expressed in the dorsal blastopore lip(胚孔唇 Spemann organizer)of the gastrula(原肠胚) were cloned. ben--CDNA library Organizer-specific Genes dissected dorsal lip st 10 y4 gastrula

Fig. 4a Genes specifically expressed in the dorsal blastopore lip (胚孔唇Spemann organizer) of the gastrula（原肠胚）were cloned. Organizer-specific Genes

Chordin(脊索发生素) mRNA is expressed in Spemann’s organIzer. Chordin protein is secreted and diffuses in the embryo

Chordin（脊索发生素）mRNA is expressed in Spemann’s organizer. Chordin protein is secreted and diffuses in the embryo. Fig. 4b

Chordin is an antagonist(拮抗剂) that binds BMP growth factors in the extracellular space, inhibiting binding to cell surface receptors. Chordin establishes a BMP4 activity gradient at gastrula. Another protein, Noggin(头发生素), has similar activity Secreted antagonists diffuse and are used in development to generate morphogen gradients BMP4 +chd Chd or Cerberus Chordal inhibits Fig 5

Chordin is an antagonist（拮抗剂）that binds BMP growth factors in the extracellular space, inhibiting binding to cell surface receptors. Chordin establishes a BMP4 activity gradient at gastrula. Another protein, Noggin（头发生素）, has similar activity. Secreted antagonists diffuse and are used in development to generate morphogen gradients. Chordin inhibits Fig. 5