Document Detail

Congenital heart disease and the specification of left-right asymmetry.
MedLine Citation:
PMID:  22408017     Owner:  NLM     Status:  MEDLINE    
Complex congenital heart disease (CHD) is often seen in conjunction with heterotaxy, the randomization of left-right visceral organ situs. However, the link between cardiovascular morphogenesis and left-right patterning is not well understood. To elucidate the role of left-right patterning in cardiovascular development, we examined situs anomalies and CHD in mice with a loss of function allele of Dnaic1, a dynein protein required for motile cilia function and left-right patterning. Dnaic1 mutants were found to have nodal cilia required for left-right patterning, but they were immotile. Half the mutants had concordant organ situs comprising situs solitus or mirror symmetric situs inversus. The remaining half had randomized organ situs or heterotaxy. Looping of the heart tube, the first anatomical lateralization, showed abnormal L-loop bias rather than the expected D-loop orientation in heterotaxy and nonheterotaxy mutants. Situs solitus/inversus mutants were viable with mild or no defects consisting of azygos continuation and/or ventricular septal defects, whereas all heterotaxy mutants had complex CHD. In heterotaxy mutants, but not situs solitus/inversus mutants, the morphological left ventricle was thin and often associated with a hypoplastic transverse aortic arch. Thus, in conclusion, Dnaic1 mutants can achieve situs solitus or inversus even with immotile nodal cilia. However, the finding of abnormal L-loop bias in heterotaxy and nonheterotaxy mutants would suggest motile cilia are required for normal heart looping. Based on these findings, we propose motile nodal cilia patterns heart looping but heart and visceral organ lateralization is driven by signaling not requiring nodal cilia motility.
Richard J B Francis; Adam Christopher; William A Devine; Lawrence Ostrowski; Cecilia Lo
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2012-03-09
Journal Detail:
Title:  American journal of physiology. Heart and circulatory physiology     Volume:  302     ISSN:  1522-1539     ISO Abbreviation:  Am. J. Physiol. Heart Circ. Physiol.     Publication Date:  2012 May 
Date Detail:
Created Date:  2012-05-16     Completed Date:  2012-07-26     Revised Date:  2013-06-26    
Medline Journal Info:
Nlm Unique ID:  100901228     Medline TA:  Am J Physiol Heart Circ Physiol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  H2102-11     Citation Subset:  IM    
Department of Developmental Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15201, USA.
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MeSH Terms
Axonemal Dyneins / genetics,  physiology
Body Patterning / genetics*,  physiology
Ciliary Motility Disorders / complications,  genetics,  physiopathology
Heart Defects, Congenital / genetics*,  physiopathology
Mice, Inbred C57BL
Mice, Mutant Strains
Models, Animal
Morphogenesis / genetics*,  physiology
Signal Transduction / genetics,  physiology
Situs Inversus / genetics*,  physiopathology
Grant Support
Reg. No./Substance:
EC Dyneins; EC protein, mouse

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