Hyperglycemia impairs left-right axis formation and thereby disturbs heart morphogenesis in mouse embryos

被引：23

作者：

Hachisuga, Masahiro ^{[1
]}

Oki, Shinya ^{[1
]}

Kitajima, Keiko ^{[1
]}

Ikuta, Satomi ^{[1
]}

Sumi, Tomoyuki ^{[1
]}

Kato, Kiyoko ^{[2
]}

Wake, Norio ^{[2
]}

Meno, Chikara ^{[1
]}

机构：

[1] Kyushu Univ, Grad Sch Med Sci, Dept Dev Biol, Fukuoka 8128582, Japan

[2] Kyushu Univ, Grad Sch Med Sci, Dept Obstet & Gynecol, Fukuoka 8128582, Japan

来源：

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA | 2015年 / 112卷 / 38期

关键词：

diabetes; congenital heart defects; heterotaxia; left-right axis; LEFT-RIGHT ASYMMETRY; NEURAL-TUBE DEFECTS; NODAL EXPRESSION; EARLY EMBRYOGENESIS; DIABETIC PREGNANCY; LATERAL PLATE; PITX2; GENE; BODY; ESTABLISHMENT;

D O I：

10.1073/pnas.1504529112

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Congenital heart defects with heterotaxia are associated with pregestational diabetes mellitus. To provide insight into the mechanisms underlying such diabetes-related heart defects, we examined the effects of high-glucose concentrations on formation of the left-right axis in mouse embryos. Expression of Pitx2, which plays a key role in left-right asymmetric morphogenesis and cardiac development, was lost in the left lateral plate mesoderm of embryos of diabetic dams. Embryos exposed to high-glucose concentrations in culture also failed to express Nodal and Pitx2 in the left lateral plate mesoderm. The distribution of phosphorylated Smad2 revealed that Nodal activity in the node was attenuated, accounting for the failure of left-right axis formation. Consistent with this notion, Notch signal-dependent expression of Nodal-related genes in the node was also down-regulated in association with a reduced level of Notch signaling, suggesting that high-glucose concentrations impede Notch signaling and thereby hinder establishment of the left-right axis required for heart morphogenesis.

引用

页码：E5300 / E5307

页数：8

共 56 条

[1] Differential regulation of node formation, nodal ciliogenesis and cilia positioning by Noto and Foxj1 [J].

Alten, Leonie ;

Schuster-Gossler, Karin ;

Beckers, Anja ;

Groos, Stephanie ;

Ulmer, Baerbel ;

Hegermann, Jan ;

Ochs, Matthias ;

Gossler, Achim .

DEVELOPMENT, 2012, 139 (07) :1276-1284

[2] Nodal activity in the node governs left-right asymmetry [J].

Brennan, J ;

Norris, DP ;

Robertson, EJ .

GENES & DEVELOPMENT, 2002, 16 (18) :2339-2344

[3] Biochemistry and molecular cell biology of diabetic complications [J].

Brownlee, M .

NATURE, 2001, 414 (6865) :813-820

[4] Diabetic Embryopathy: A Developmental Perspective from Fertilization to Adulthood [J].

Castori, M. .

MOLECULAR SYNDROMOLOGY, 2013, 4 (1-2) :74-86

[5] Oxidant regulation of gene expression and neural tube development: Insights gained from diabetic pregnancy on molecular causes of neural tube defects [J].

Chang, TI ;

Horal, M ;

Jain, SK ;

Wang, F ;

Patel, R ;

Loeken, MR .

DIABETOLOGIA, 2003, 46 (04) :538-545

[6] TERATOGENIC EFFECTS OF EXCESS GLUCOSE ON HEAD-FOLD RAT EMBRYOS IN CULTURE [J].

COCKROFT, DL ;

COPPOLA, PT .

TERATOLOGY, 1977, 16 (02) :141-146

[7] Relationship between asymmetric nodal expression and the direction of embryonic turning [J].

Collignon, J ;

Varlet, I ;

Robertson, EJ .

NATURE, 1996, 381 (6578) :155-158

[8] Diabetes mellitus and birth defects [J].

Correa, Adolfo ;

Gilboa, Suzanne M. ;

Besser, Lilah M. ;

Botto, Lorenzo D. ;

Moore, Cynthia A. ;

Hobbs, Charlotte A. ;

Cleves, Mario A. ;

Riehle-Colarusso, Tiffany J. ;

Waller, Kim ;

Reece, E. Albert .

AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY, 2008, 199 (03) :237.e1-237.e9

[9] Congenital Heart Defects in Europe Prevalence and Perinatal Mortality, 2000 to 2005 [J].

Dolk, Helen ;

Loane, Maria ;

Garne, Ester .

CIRCULATION, 2011, 123 (08) :841-U46

[10] Characterization of Pitx2c Expression in the Mouse Heart Using a Reporter Transgene [J].

Furtado, Milena B. ;

Biben, Christine ;

Shiratori, Hidetaka ;

Hamada, Hiroshi ;

Harvey, Richard P. .

DEVELOPMENTAL DYNAMICS, 2011, 240 (01) :195-203

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