Abstract 19609: Novel Wnt Signaling in Neonatal Heart During Perinatal Transition
Background: Fetal to neonatal transition of the mammalian heart is an elaborate process, during which the neonatal cardiomyocytes undergo complete maturation, differentiation, and irreversible exit from the cell cycle. However, the molecular mechanisms that control the chamber specific- growth of postnatal heart are understudied. In particular, the permanent arrest of cardiomyocytes cycling remains mysterious both in terms of the etiology and the mechanisms.
Objectives: To determine factors of chamber specificity in neonatal heart during postnatal growth and maturation.
Methods: Deep RNA-seq (2x92nt) was performed on male newborn mouse left ventricle (LV) and right ventricle (RV) at P0, P3 and P7. Neonatal Rat Ventricular Myoctes (NRVM), Wnt11-siRNA, and recombinant Wnt11 (rWnt11) were used to achieve Wnt11 Inhibition and gain of function respectively In Vitro. Wnt11-Antisense oligo nucleotide was used to achieve In Vivo inhibition of Wnt11. Anti-Phospho histone3 (Ph3) was used to assess proliferation.
Results: Extensive transcriptome analysis and experimental validation revealed distinct, chamber specific- patterns of temporal regulation of cell cycle genes and Wnt signaling during maturation. Specifically, an RV specific- induction of cell cycle genes was found to reciprocally correlate with a robust LV specific- enrichment of the non-canonical-Wnt11 at P7. Functional studies revealed enhancement of NRVM maturation markers and down-regulation of cell cycle genes in response to Wnt11 gain of function. In contrast, Wnt11 inhibition induced NRVM proliferation markers and reduced the size and the fraction of bi-nucleated cells supporting a functional impact of wnt11. Furthermore, InVivo inhibition of Wnt11 at late gestation enhanced Ph3 and cell cycle markers at P0 suggesting cellular proliferation.
Conclusions: Our findings suggest novel molecular basis for chamber-specific programming of proliferation and maturation in neonatal heart, including differential enrichment of cell cycle genes and novel Wnt11-mediated signaling. Further mechanistic studies to decipher putative roles of Wnt11 signaling in LV vs. RV programming during maturation in Vivo will likely pave the way to novel chamber-specific therapeutic targets.
Author Disclosures: M. Touma: None. X. Kang: None. A. Cass: None. X. Xiao: None. Y. Wang: None.
This research has received full or partial funding support from the American Heart Association.
- © 2014 by American Heart Association, Inc.