Mechanistic study of signal transduction in heart development

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1 Chinese Bulletin of Life Sciences Vol. 19, No. 4 Aug., (2007) [1] ( ) [2] ANF β-mhc [1-2] R541; Q132.4; Q954.4 A Mechanistic study of signal transduction in heart development CHANG Zai, YANG Zhongzhou* (Model Animal Research Center of Nanjing University, Nanjing , China) Abstract: In China, the population quality is deteriorating by high rate of birth defects, among which congenital heart diseases are the most common. Similarly, postnatal cardiovascular disorders are becoming the main impediment to population health and social development. Recent studies have demonstrated that developmental biology is involved in the pathogenesis of postnatal cardiovascular disorders in that hereditary factors contribute to the progress of these diseases, although they fail to cause embryonic abnormalities. The fact that in some postnatal cardiovascular diseases, essential genes for embryogenesis such as ANF and beta-mhc are activated indicates that certain embryonic developmental mechanisms are engaged in the pathogenesis. Because the prevention of birth defects and cardiovascular disorders is one of the major issues that demands urgent solution for public health and social development, the understanding of normal developmental mechanisms and knowledge as well as pathogenesis of cardiovascular system is becoming increasingly important for the purpose to help establish novel and efficient strategy and measures of prevention. Here we briefly summarize the current research proceedings of signal transduction regulation in heart development of commonly used model animals with emphasis on mouse. Key words: heart; cardiovascular diseases; congenital heart diseases; embryogenesis; model animals (2006CB943500) (1979 ) (1970 ) * yangzz@nicemice.cn

2 354 1 ( lateral plate mesoderm) (cardiac progenitor) (angioblast) [3-4] (1) (2) (3) (4) ( 1) [5-8] NK2 MEF2 GATA Tbx Hand ( 2) (patterning) (morphogenesis) [6] vasculogenesis angiogenesis vasculogenesis angiogenesis ( vasculogenesis angiogenesis ) [9] (splanchnic mesoderm ) (angioblast hemangioblast ), (primary capillary plexus) FGF2 VEGF Ang-1 VEGF TGF PDGF [9] [6-8] 90% [10] ( ) ( ) [11] 1 [5] d(e7.75-e12) A Hand2 LacZ (cardiac crescent); B-D E-H E-G (β-gal staining LacZ Hand2 Nkx2.5 ) (E) (F) (G) H hf head folds ba branchial arch ra right atrium la left atrium rv right ventricle lv left ventricle cp cardiac progenitors ht heart nt neural tube

3 355 [3-4,7-8] (1) ( ) (2) (cardiac neural crest) - (3) (progenitor cells) (4) [8], Morgan 100 [6] [6,8] ( 2) [6-8] (redundancy) 2 [6] [6] [10] (reporter) (LacZ ) EGFP [13-14] Nkx2.5 EGFP Nkx2.5 [13-14] Wnt-11 Wnt-11 EGFP EGFP [14] [12-13] 2.1.3

4 356 90% ( ) [10,15] [11,15] / [7-8] [3] [4-5] (1) (2) (3) (4) [4-5] (1) TGF-β BMP-2 4 Wnt FGF8 [6,13] Wnt [7] BMP-Smad5-Nodal FGF8-Nodal- Smad2/3 Shh-Lefty [3-4,7] Ras-Raf-MPAK PI3K/Akt Jak/STAT G- [3-4,20] / ( ) [3,5] 7.5 d ( ) (cardiac crescent) TGF (BMP-2) FGF2 BMP-4 [3,7-8] Wnt (homeobox gene) Nkx2.5 Nkx2.5 GATA [7,9] Nkx2.5 GATA (GATA4/5/6) [16-17] (first heart field, FHF primary heart field, PHF) (secondary heart field, SHF) ( ) [6-8] FGF10 Hand2 [8] ( ) ( ) [3] Wnt-11 [14] Wnt-11

5 357 GATA GATA-4 GATA-5 GATA-6 Mesp1 Mesp2 Hand2 [18] GATA GATA GATA-1 GATA-2 GATA-3 GATA-4 GATA- 5 GATA-6 GATA-4 GATA-6 GATA-6 ( d) ( ) [17,19] GATA-4 (8 9 d) Mesp (bhlh) Mesp1 [17-19] [16-19] ( ) ( ) [3] (pattern formation) (1) ( ) (2) ( ) (3) ( ) ( ) [3,7] BMP-Smad5-Nodal Shh-Lefty1-Smad2/3 FGF-8-Smad2/3-Pitx2 [16-19] Pitx2 Nkx3.2 Hand1 Hand2 Mef2c ANF Pitx2 FGF-8-Smad2/ (morphogenesis) [16,18-19] BMP ANF SERCA Chisel MLC2 α-mhc Irx4/5 Hand1 Tbx5 [18-19] Ras-Raf-MAPK PI3K/ Akt RhoA/ROCK GPCR JAK/ STAT [20] [4] ( 2) ( ) (identity) 3.2 MicroRNA RNA(small RNA) Hand2 Zhao [21-22] MicroRNA Hand2 Messenger RNA MicroRNA [23] 3.3

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