Congenital heart defects (CHD) are a leading cause of morbidity and mortality in infants and comprise a frequent class of congenital anomalies, yet little is known about the underlying genetic basis. Atrioventricular Septal Defects (AVSDs) represent the most common form of Congenital Heart Disease (CHD) in people with Down Syndrome (DS), with AVSD incidence of ca. 20%. Trisomy 21 carries a 2000-fold increased risk for AVSDs compared to the euploid population, which has not been explained at either the genetic or developmental level. We apply recent progress in DS and AVSD pathophysiology to address a novel hypothesis that cilia and sonic hedgehog (Shh) signaling is paramount to the occurrence of ASVDs in DS. The developmental paradigm for atrioventricular septation has undergone recent revision based on work in the Moskowitz laboratory 1-3 and others 1-4. Whereas the canonical view of atrioventricular septation was based on endocardial cushion development with an emphasis on the cardiac valve anlage, recent results demonstrate that cilia-based Hedgehog signaling in the second heart field (SHF) is essential for this process1-41-4. Further, the Reeves lab found that two populations of embryonic cells, cerebellar granule cell precursors (gcp) and cranial neural crest cells, have attenuated response to Shh in trisomic mice 5,6. Thus, cilia-based Hedgehog signaling has been implicated in AVSDs and a Hedgehog signaling decrement has been observed in DS cells. We will interrogate the hypotheses that Hedgehog signaling and cilia function is disrupted by trisomy, resulting in increased AVSD risk in DS mouse models. The ultimate aim of this work is improved understanding of the genetic and developmental causes of AVSDs in DS with the potential to shed mechanistic light on AVSD causation more generally.

Public Health Relevance

Congenital heart disease (CHD) is a leading cause of morbidity and mortality in infants, yet little is known about its causes;in particular, individual with trisomy 21, or Down syndrome (DS), are particularly sensitized toward abnormal heart development. We will interrogate the hypotheses that Hedgehog signaling and cilia function is disrupted by trisomy, resulting in increased CHD risk in DS mouse models. Our goal is to use this knowledge in prevention and treatment of CHD-conditions for all people.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Genetics of Health and Disease Study Section (GHD)
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Schramm, Charlene A
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University of Chicago
Schools of Medicine
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Steimle, Jeffrey D; Rankin, Scott A; Slagle, Christopher E et al. (2018) Evolutionarily conserved Tbx5-Wnt2/2b pathway orchestrates cardiopulmonary development. Proc Natl Acad Sci U S A 115:E10615-E10624
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Zhou, Lun; Liu, Jielin; Xiang, Menglan et al. (2017) Gata4 potentiates second heart field proliferation and Hedgehog signaling for cardiac septation. Proc Natl Acad Sci U S A 114:E1422-E1431
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Burnicka-Turek, Ozanna; Steimle, Jeffrey D; Huang, Wenhui et al. (2016) Cilia gene mutations cause atrioventricular septal defects by multiple mechanisms. Hum Mol Genet 25:3011-3028
Potier, Marie-Claude; Reeves, Roger H (2016) Editorial: Intellectual Disabilities in Down Syndrome from Birth and Throughout Life: Assessment and Treatment. Front Behav Neurosci 10:120
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