“IMPORTANT” GENES- 点击: 作者: 来源: 日期:2006-11-09 本站论坛
Preimplantation Development
- Oct4 – transcription factor expressed in ICM, necessary for development of ICM and proliferation of trophectoderm (via of regulation of Fgf4 expression). (Autonomous)
- Fgf4 - transcription factor expressed in ICM that is crucial for trophectoderm proliferation (non-autonomous – activated by Oct4)
Principles of Development
- White/c-kit – receptor tyrosine kinase crucial for neural crest cell and primordial germ cell migration, binds to steel which functions as chemoattractant – defects are cell autonomous
- Steel/c-kit ligand – secreted protein crucial for neural crest cell and primordial germ cell migration, binds to c-kit on surface of migrating cells – defects are cell non-autonomous
Drosophila Patterning
- Bicoid – transcription factor localized to anterior pole of Drosophila egg, anterior localization controls gene expression in anterior of syncitial embryo (formation of transcription factor gradients before cellularization)
- Nanos – posterior determinant of Drosophila egg, localized to posterior pole
- Hunchback – transcription factor whose level along a/p axis of Drosophila embryo is controlled by bicoid and nanos – threshold level of bicoid required to activate hunchback transcription, translation of hunchback mRNA inhibited by nanos (high level in anterior, low levels in posterior) – controls expression of gap genes (acts and activator and repressor of the same genes based on concentration)
- Kruppel – gap gene (transcription factor), repressed by high [hunchback], activated at intermediate [hunchback]
- Knirps – gap gene (transcription factor), repressed by hunchback but active at low [hunchback] – also has anterior stripe elements controlled by different enhancers and transcription factors – expression repressed by tailless at posterior end
- Giant – gap gene (transcription factor), repressed by hunchback, only active and very low [hunchback] - also has anterior stripe elements controlled by different enhancers and transcription factors - expression repressed by tailless at posterior end
**Gap genes control expression of pair rule genes. Pair rule genes control the expression of other pair rule genes and of segment polarity genes. Gap genes, pair rule genes, and segment polarity genes influence expression of homeotic genes, which work with d/v determinants to determine what structures go where.**
- Dorsal – transcription factor whose expression is uniform throughout Drosophila embryo but has graded nuclear localization (localized to nucleus on ventral side, not localized on dorsal side) – activates ventrally expressed genes (twist/snail), represses dorsally expressed genes – nuclear localization prevented on dorsal side by gurken (secreted growth factor) from dorsal embryo, which signals follicular cells and prevents secretion of molecules mediating dorsal nuclear localization Spatzle/Toll à (Tolloid, Zorknult, Decapentalogic)
- Pair rule genes – primary pr genes regulated by gap genes, secondary pr genes regulated by primary pr genes, expression of primary and secondary pr genes is “out of phase,” creating unique expression pattern in each row of cells
- Hairy – Drosophila pair rule gene, single gene expressed in 7 stripes with each stripe controlled by a different enhancer through combination of activation and repression – transcription factor – stripe 6: activated by knirps and repressed by kruppel
- Even-skipped – Drosophila pair rule gene – transcription factor – stripe 2: activated by bicoid and hunchback, repressed by giant and kruppel
- Segment polarity genes – encode extracellular signalling proteins, transmembrane proteins, serine-threonine kinases, transcription factors, adhesion proteins – expressed just prior to cellularization and throughout embryogenesis, expressed in identical patterns in each segment (Ex. Engrailed (transcription factor) and hedgehog (signalling molecule) in anterior, wingless (signalling molecule) in posterior – expression of all 3 is interdependent)
- Homeotic genes – transcription factors – expression controlled by gap, pair rule, and segment polarity genes – spatial (a/p) and temporal expression patterns regulate structures in each segment (Ex. Scr controls a/p localization of salivary gland formation)
Vertebrate Patterning
- Mammalian Hox genes – control a/p patterning – 4 complexes (arose through gene duplication) with 13 different gene “paralogs” repeated in 4 complexes (38 genes total), multiple copies leads to functional redundancy – colinearity in terms of spatial and temporal expression and retinoic acid sensitivity
- Sonic hedgehog – signaling molecule expressed by notochord to induce ventral formation of floor plate and motor neurons (ventral cell types), later expressed by floor plate for further induction of ventral patterning; also important in d/v patterning of somite: induces sclerotome (most ventral portion of somite), low sonic hedgehog with Wnt1 (from dorsal neural tube) induces myotome
- BMP – TGFβ superfamily member - induces neural crest and other dorsal cell types in neural tube, expressed in embryonic ectoderm dorsal to neural tube)
Gastrulation
- FGF – signaling plays a role in movement of primitive streak
- Smad 2 – transcription factor required for formation of primitive streak (a/p gene expression in visceral endoderm and embryo), translocates to nucleus to activate transcription of target genes when phosphorylated by signal transduction pathway initiated by binding of TGFβ-like growth factor (nodal?) to surface receptor
- Nodal – TGFβ superfamily member crucial for mesoderm induction – expressed in embryo in response to extraembryonic signalling, upregulates own expression and induces Smad2-dependent changes in gene expression in distal visceral endoderm (which will migrate to form anterior visceral endoderm that prevents anterior primitive streak formation in the embyo) – also important for left/right asymmetry of embryo (specifically, heart and internal organs)
Central Nervous System
- Delta/Notch – inhibitor of neural differentiation (represses neurogenin)
- Netrins – secreted by floor plate (DCC receptor – chemoattractant)
- Slit/Robo – ligand/receptor, repels neurons from plate after exit
- Neutrophins – postsynaptic secretions, induce survival of neurons
- Nogo – CNS white matter protein responsible for limiting nerve regeneration
Muscle
- MyoD – myogenic determination factor (induced by Pax3)
- Myogenin/MEF – terminal muscle cell differentiation factors
- Pax3 – regulates MyoD, repressed by notochord. Decrease Pax3 à Myo D induced muscle differentiation
Bone
- GDF/BMP – induce bone formation, growth, size
- Pax1 – induced by Shh in sclerotome, induces bone formation
- Sox9 – induces cartilage to bone transformation
- Ihh/PRP – activates chonrdocyte proliferation, repressed cartilage à bone
- Fox/src – mutant osteoclasts/functionless osteoclasts
Limb Development
- HNF3β – transcription factor expressed in primitive node, important for d/v patterning of neural tube and l/r patterning of embryo
- FGF10 – expressed in mesoderm underlying limb bud in response to Wnt6, induces expression of FGF8 and other FGFs in apical ectodermal ridge (AER)
- FGF8 – induced by FGF10, expressed in AER prior to limb bud outgrowth, acts on underlying mesoderm to maintain FGF10 and induce sonic hedgehog (which then induces other FGFs in AER)
- KIF-3B – microtubule-dependent motor expressed in cilia in primitive node – cilia move in direction to create leftward flow which may be important in asymmetric distribution of transcription factors (ex. Lefty-2) to create l/r asymmetry
- Ptc (patched) – transmembrane protein that negatively regulates sonic hedgehog signalling, inactivated by sonic hedgehog – tumor suppressor because loss of Ptc function leads to constitutive activation of sonic hedgehog signalling
- Smo (smoothened) – transmembrane protein blocked by Ptc, activates sonic hedgehog signalling in absence of Ptc – oncogene because constitutive Smo activation leads to constitutive activation of sonic hedgehog signaling
Neural Crest
- BMP6(dorsal neural tube) & Wnt6 (ectodermal cells) – differentiate cell fates
- Steel/cKit – migration, melanocytes
- EDN3/EDN3R – migration melanocytes, enteric neurons
Eye
- Pax6 – development of lens placode (mutation à aniridia)
- BMP4,6 – secreted from neural tube, induces lens formation on ectoderm
- FGF1,2 – secreted from lens, induces retinal formation
- Engrailed – expressed A à P gradient setting up nasal à temporal gradient
Nose
· Pax6 – development of olfactory placode on ectoderm
Vasculogenesis/Angiogenesis
· VEGF – expressed by endoderm, binds to VEGFR on angioblasts, induces angiogenesis/vasculogenesis
· TIE 1,2 – receptor (binds angiopoietin), recruitment of mesenchyme for vessel genesis
Heart
- Nkx2.5 – marker for embryonic cardiac cells
- BMP2 – expressed by endoderm, induces mesoderm lateral plate differentiation
- AMHC/VMHC – atrioventricular differentiation
- Nodal – Shh induces nodal on left side only for L/R asymmetry of heart
- eHand – Nkx2.5 induced, activates MEF2C, left vent expansion
- dHand – activates MEF2C, right vent expansion
Kidney
- BMP4 – ectoderm expression, activates Lim1, Pax2, Sim1, for early intermediate mesoderm differentiation
- GDNF – expressed by metanephric mesenchyme, induces outgrowth of utreteric bud
- RAF – released by kidney stromal cells, binds RET on ureteric bud à secretes LIF, FGF2, BMP7 for mesenchyme conversion to epithelium
- WT1 – (Wilm’s Tumor Suppressor) expressed by mesenchyme, stimulates ureteric bud outgrowth, differentiation
Sex Determination
· Steel/TGFb - germ cell migration
· SRY (TDF) – Y chromosome gene essential for testes development
· MIS – produced by Sertoli cells, induces Mullerian regression
· 5areductase – converts testosterone à DHT à 2ndary male sex character.
Gastro-Intestinal System
- Shh/Ihh – expressed by endoderm, activates BMP4/Patched à inhibits smooth muscle/neuron differentiation proximal to inner endoderm
Liver
- FGF – expressed by cardiac mesoderm, induces differentiation of hepatic endoderm
- BMP - expressed by septum transversum, induces differentiation of hepatic endoderm
- Hex – induces invasion of hepatoblasts into STM
- Prox1 – induces cadherins on hepatoblasts
- VEGF – bind fIK1 receptor, induce vasculogensesis in liver
- HNF 1,6 – induces hepatocyte formation (in place of bile duct cholaryocyte)
Pancreas
- Pdx1 – pancreas development (expressed in absence of Shh)
- Notch/Delta – activation à suppression of primary fate à exocrine cells
no activation à activation of primary fate à endocrine cells
Lung
- VEGF – bind fIK1 receptor, induce vasculogensesis
- Gli – expressed by mesoderm forgut, transduces Shh, induces lung bud
- FGF10 – epressed by mesoderm, induces lung develop, bud epithelial growth
- BMP4 – expressed by endoderm, feedback inhibition of FGF10 activation
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