The molecular mechanisms regulating sympathetic innervation of the heart during embryogenesis and its importance for cardiac development and function remain to be fully elucidated. We generated mice in which conditional knockout (CKO) of the Hif1a gene encoding the transcription factor hypoxia-inducible factor 1α (HIF-1α) is mediated by an Islet1-Cre transgene expressed in the cardiac outflow tract, right ventricle and atrium, pharyngeal mesoderm, peripheral neurons, and hindlimbs. These Hif1aCKO mice demonstrate significantly decreased perinatal survival and impaired left ventricular function. The absence of HIF-1α impaired the survival and proliferation of preganglionic and postganglionic neurons of the sympathetic system, respectively. These defects resulted in hypoplasia of the sympathetic ganglion chain and decreased sympathetic innervation of the Hif1aCKO heart, which was associated with decreased cardiac contractility. The number of chromaffin cells in the adrenal medulla was also decreased, indicating a broad dependence on HIF-1α for development of the sympathetic nervous system.

German Centre for Cardiovascular Research Partner Site Munich Munich Heart Alliance 80636 Munich Germany

German Heart Centre Munich Technical University 80636 Munich Germany

Institute for Cell Engineering Johns Hopkins University School of Medicine Baltimore MD 21205

Institute of Anatomy 1st Faculty of Medicine Charles University 110 00 Prague Czechia

Institute of Dental Medicine 1st Faculty of Medicine Charles University 110 00 Prague Czechia

Institute of Physiology Czech Academy of Sciences 142 00 Prague Czechia

Laboratory of Molecular Pathogenetics Institute of Biotechnology Czech Academy of Sciences 252 50 Vestec Czechia

Laboratory of Molecular Pathogenetics Institute of Biotechnology Czech Academy of Sciences 252 50 Vestec Czechia;

McKusick Nathans Institute of Genetic Medicine Johns Hopkins University School of Medicine Baltimore MD 21205;

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