1Anterior/PosteriorAxis FormationDevelopmental Biology 7.72Sylvain LapanScott ValastyanWarren WhyteThe Anterior/Posterior Axis2Retinoic Acid• Regulates gene expression in numerous celltypes• RA plays a crucial role in embryogenesis• Dysregulation of RA levels leads to severemalformationRegulation of Retinoic Acid LevelsMarletaz et al. (2006)3Deuterostome Phylogeny and Conservationof RA Signaling ComponentsMarletaz et al. (2006)Retinoic Acid Signaling Pathway4Retinoic Acid InducesPosteriorizationMarletaz et al. (2006)Maden et al (1989)• CRABP found in ecto-,mesodermal cells(RA?)• [RA] high in neural crest region• Likely secreted from dorsal blastopore lip• Nieuwkoop center indirectly involved in RAregulation• Homoebox genes5Cracking the Hox Code• Hox genes encode TFs that regulate embryonicdevelopment• Its responsiveness corresponds with its locationwithin the gene cluster (4 + 13)• 3’ end genes= low RA• 5’ end genes= high RA• Expression pattern of Hox genes correspondlinearly with gene order along DNA***• time of onset + code = pos. addressChromosomal Organization and SchematicExpression of Hox ClustersStern et al. (2006)6Distinct Roles for Fgf, Wnt andRetinoic Acid in Posteriorizing theNeural EctodermT. Kudoh, S. Wilson, and I. DawidDevelo pment 129:4335-4346 (2002)Definitions• Epiboly = Ectodermal cell movementduring gastrulation around the yolk• Blastoderm Margin = Interface betweenthe blastoderm and the yolk• Negative Feedback Loop = The ability ofa signaling molecule to downregulate itsown expression by activating its owninhibitor7Gastrulation in ZebrafishF i g u r e 2 ! G a s t r u l a t i o n m o v e m e n t s . (a) D o m e s t a g e . C e l l s i n t e r c a l a t e r a d i a l l y , c o n t r i b u t i n g t o e p i b o l y . (b) S h i e l d s t a g e .C e l l s a t t h e m a r g i n i n t e r n a l i z e a n d m i g r a t e t o w a r d t h e a n i m a l p o l e . C e l l s c o n v e r g e d o r s a l l y , w i t h l a t e r a l m e s o d e r m a l c e l l ss t a r t i n g c o n v e r g e n c e a t l a t e r s t a g e s t h a n c e l l s c l o s e r t o t h e s h i e l d . (c) 9 0 % e p i b o l y s t a g e . E p i b o l y , i n t e r n a l i z a t i o n ,c o n v e r g e n c e a n d e x t e n s i o n c o n t i n u e . M o d i fi e d f r o m R e f e r e n c e .8Dominant-Negative Mutants• A dominant mutation that blocks theactivity of a wild type allele at the samegene (i.e., the mutant blocks wt activity)Alberts et al., 4th edition9FGF SignalingLloyd (2006)1011LiCl = Activates Wnt signaling by inhibiting GSK3, thusstabilizing !-cateninDkk1 overexpression = Inhibits Wnt signaling byantagonistically binding to Wnt co-receptors (Lee et al., 2004)1213Morpholino AntisenseOligonucleotides• DNA analogs that that use Watson-Crickbasepairing to sequester a specific mRNA,thus preventing its translation• Knock-down approach1415In red: additional relationships suggested by this study.The Figure numbers refer to the particular data that suggest each relationship. Relationships whichnot have been explicitly demonstrated, but nonetheless are consistent with the authors’ data, areindicated with a “?”.1) Figure 4H; 2) Figure 6L shows this effect isindependent of FGF; 3) Figure 8C shows this effectis independent of Wnt ?Figure 4HFigure 4BStern et al. (2006)3 Models to Explain A/P
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