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Experiment

Echocardiography Order #939 8/1/05

Summary

Data Summary

Investigator	Bader, David
Description	CENP-F is a large multifunctional protein with demonstrated regulatory roles in cell proliferation, vesicular transport and cell shape through its association with the microtubule (MT) network. Until now, analysis of CENP-F has been limited to in vitro analysis. Here, using a Cre-loxP system, we report the in vivo disruption of CENP-F gene function in murine cardiomyocytes, a cell type displaying high levels of CENP-F expression. Loss of CENP-F function in developing myocytes leads to decreased cell division, blunting of trabeculation and an initially smaller, thin-walled heart. Still, embryos are born at predicted mendelian ratios on an outbred background. After birth, hearts lacking CENP-F display disruption of their intercalated discs and loss of MT integrity particularly at the costamere; these two structures are essential for cell coupling/electrical conduction and force transduction in the heart. Inhibition of myocyte proliferation and cell coupling as well as loss of MT maintenance is consistent with previous reports of generalized CENP-F function in isolated cells. One hundred percent of these animals develop progressive dilated cardiomyopathy with heart block and scarring, and there is a 20% mortality rate. Importantly, although it has long been postulated that the MT cytoskeleton plays a role in the development of heart disease, this study is the first to reveal a direct genetic link between disruption of this network and cardiomyopathy. Finally, this study has broad implications for development and disease because CENP-F loss of function affects a diverse array of cell-type-specific activities in other organs. Applicable research area(s): Cardiovascular
Status	Completed
Public Release	9/18/2010
Animal Age	Measured In: week(s) post-natal (w)
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Data Analysis

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Type	Count
Animals	18
Experimental Conditions	1
Catalog Items	1
Curation Info (# flags)	2
Phenotype Assays	11
Phenotype Measurements	153
Histology Images	0
Publications	0

Animals

Strain Name	Common Name	Females	Males	Unknown
C57BL/6J	C57BL/6J	2	3	0
C57BL/6-Cenpf^tm1Dbdr Tg(Tnnt2-cre)5Blh	C57BL/6-Cenpf^tm1Dbdr Tg(Tnnt2-cre)5Blh	10	3	0

Animals/Strains

Experimental Factors

	Categorical Values
	Name / Abbreviation	Description
	Experimental Factor: Experimental Group
	Control	This animal belongs to the control group for the experiment.
	Experiment	This animal belongs to experimental group that is homozygous for gene manipulations.

Experimental Factor (Units)
Experimental Group

Experimental Factor Values

Phenotype Assays Add / Edit

Name	Abbreviation
body mass	W rodent
fractional shortening	fractional shortening
heart rate	HR
left ventricle mass	left ventricle mass
cardiac ejection fraction	cardiac ejection fraction
left ventricle internal diameter end-diastole	left ventricle internal diameter end-diastole
left ventricle internal diameter end-systole	left ventricle internal diameter end-systole
left ventricle posterior wall thickness end-diastole	LVPWT-end diaastole
left ventricle posterior wall thickness end-systole	LVPWT-end systole
left ventricle septal wall thickness end-diastole	LVSWT-end diastole
left ventricle septal wall thickness end-systole	LVSWT-end systole

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