REGULATION OF CARDIAC MORPHOGENESIS

Project: Research project

Description

Congenital heart defects (CHDs) affect almost 1% of all live human births and frequently require intervention
in order to prevent death. Although the deleterious consequences of such cardiac malformations are usually
evident after birth, the causes of these congenital defects frequently involve disregulation of events within the
transcriptional programs that control cardiac specification, patterning, differentiation and morphogenesis.
Handl and Hand2 are evolutionary conserved basic Helix-Loop-Helix (bHLH) transcription factors that
exhibit partially overlapping spatiotemporal expression patterns during cardiac development. Handl and
Hand2 are initially co-expressed, but following looping; Handl is predominantly restricted to predominantly
the left ventricle, whereas Hand2 to the right ventricle. However, both genes remain co-expressed in the
aortic sac, outflow tract (OFT) and the interventricular septum. To test whether Handl and Hand2 have
distinct biological functions, we generated Hand1-to-Hand2 knockin chimeric pups. High percentage
chimeras die at birth and exhibit hypoplastic left and right ventricles, double-outlet right ventricle (DORV),
and both muscular and membranous interventricular septal defects (VSDs). The observed phenotypes occur
specifically where endogenous Handl is expressed, suggesting that primary defects in Hand-mediated
chamber patterning during early heart development is the root cause of these neonatal CHDs. These data
support our hypothesis that Handl and Hand2 convey unique transcriptional regulation during cardiogenesis.
In addition to differential expression, Hand proteins can also dimerize with a number of potential bHLH
partners (E-proteins, Twist-family, and Hey2) providing yet another regulatory mechanism. Our goals are to
identify the distinct functional domains in Handl and Hand2 proteins that convey the observed unique
functions and to gain a better understanding of the molecular mechanism/s that underlie the CHDs observed
in the Hand1-to-Hand2 knockin pups. Specific Aim 1:Will determine if the cardiovascular anomalies in the
Hand1-to-Hand2 mutants are the result of alterations in cell proliferation, survival, or specification of the left
and right ventricular cardiomyocytes and/or colonizing cardiac neural crest. Specific Aim 2 will determine
what motifs distinguish Handl and Hand2 function and how Handl and 2 functionally interact with Hey2.
StatusFinished
Effective start/end date4/1/074/30/13

Funding

  • National Institutes of Health: $2,193,288.00
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health: $2,163,330.00
  • National Institutes of Health
  • National Institutes of Health: $2,157,033.00
  • National Institutes of Health
  • National Institutes of Health: $2,269,452.00
  • National Institutes of Health
  • National Institutes of Health: $2,150,921.00
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health

Fingerprint

Cardiac Myocytes
Heart Failure
Congenital Heart Defects
Heart Ventricles
Treatment Failure
Morphogenesis
Apoptosis
Growth
Caspase 3
Twist-Related Protein 1
Wounds and Injuries
Parturition
Hand
Double Outlet Right Ventricle
Basic Helix-Loop-Helix Transcription Factors
Cell Survival
Neural Crest
Live Birth
Myocardium
Cell Cycle

ASJC

  • Medicine(all)