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J. Rivera-Feliciano, C.J. Tabin / Developmental Biology 295 (2006) 580588

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Fig. 4. Bmp2 instructs the development of the atrioventricular canal. (A, B) Control and Bmp2Nkx2.5del

embryos at 9.5 days post-fertilization. (A) Left side view,

t h e a t r i o v e n t r i c u l a r c o n s t r i c t i o n i s a b s e n t i n m u t a n t h e a r t s ( r e d a r r o w h e a d ) . ( B ) R i g h t s i d e v i e w , t h e o u t f l o w t r a c t i s p a t t e r n e d n o r m a l l y i n B m p 2 N k x 2 . 5 d e l ( r e d a r r o w hearts h e a d ) . ( C F ) W h o l e - m o u n t i n s i t u h y b r i d i z a t i o n f o r N p p a , w h i c h m a r k s d i f f e r e n t i a t e d c h a m b e r m y o c a r d i u m i n c o n t r o l e m b r y o s . I n B m p 2 N k x 2 . 5 d e l hearts, the atrioventricular canal adopts differentiated chamber myocardium fates as judged by the expansion of Nppa into the region where the atrioventricular canal should develop (C; compare red bars). Notice the gap of expression at the atrioventricular canal in the control embryo. (DF) Nppa expression in control

and Bmp2Nkx2.5del

hearts at 9.5 days post-fertilization. Left (D), superior (E) and inferior (F) views. The position of the atrioventricular canal is indicated by the

red bar. (G, H) Tbx2 expression in control and Bmp2Nkx2.5del hearts at 9.5 days post-fertilization. The atrioventricular canal adopts differentiated chamber myocardium fates as judged by the absence of Tbx2 in the region where the atrioventricular canal should form (red bars in panels G and H). (I) Mlc2v expression, which specifically marks the ventricles and AV canal, is expanded into the atrial rudiment of Bmp2Nkx2.5del hearts.

differentiation. Interestingly, at earlier stages of heart develop- ment, Tbx2 expression actually correlates with decreased Bmp2 signaling, rather than Tbx2 being induced by BMP activity. These data come from several studies in which Tbx20 was shown to be a repressor of Bmp2 (Cai et al., 2005; Singh et al., 2005; Stennard et al., 2005). In two of these reports, the loss of Tbx20 resulted in the downregulation of Bmp2 and yet the upregulation of Tbx2 (Cai et al., 2005; Stennard et al., 2005). The third group, in contrast, found concomitant upregulation of Bmp2 and Tbx2 along the linear heart tube (Singh et al., 2005). In all three studies, embryos deficient for Tbx20 arrest at stages prior to cushion development, precluding the analysis of the relation between these genes in the later setting of cushion morphogenesis.

Bmp2 is required for specification of posterior heart structures

Prior to AV canal specification, during linear heart tube stages, Bmp2 is strongly expressed in the posterior pole of the heart where the atria develop; hence, it is possible that Bmp2 is required for atrial specification. In order to test this hypothesis, we looked at the expression of ventricular myosin light chain 2 (Mlc2v), a ventricular and AV canal-specific marker (Franco et

al., 1999). In Bmp2Nkx2.5del

hearts, Mlc2v expression is

expanded into the atrial region (Fig. 4I). As noted in Figs. 4CF, Nppa expression is dramatically upregulated in the atrial appendage of Bmp2Nkx2.5del hearts relative to controls. This high level of expression is characteristic of ventricular myocardium. Together, our data suggest that the atrial rudiment in

Bmp2Nkx2.5del

hearts is adopting the molecular identity of

ventricular myocardium. Our mutant partially phenocopies the LIM homeodomain transcription factor Isl1 mutant (Cai et al., 2003). Isl1-deficient embryos lack outflow tract, right ventricle and have mispatterned atria. Similar to our Bmp2Nkx2.5del embryos, in Isl1-deficient embryos, Mlc2v expression is expanded into the atrial appendage. This accompanies a reduction in Bmp2 expression. The authors report that this phenotype most likely arises from the failure of a particular population of cardiac progenitors that express Isl1 to migrate into these developing heart structures. Hence, our results support a model in which Bmp2 is epistatic to Isl1 and necessary for the recruitment of cardiac progenitors to the posterior heart segments. The fact that Bmp2Nkx2.5del embryos still have a properly patterned outflow tract and a normal right ventricle suggests that Isl1 regulates other targets in these anterior structures.

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