Planar cell polarity signaling regulates polarized second heart field morphogenesis to promote both arterial and venous pole septation

Abstract

The second heart field (SHF) harbors progenitors that are important for heart formation, but little is known about its morphogenesis. We show that SHF population in the mouse splanchnic mesoderm (SpM-SHF) undergoes polarized morphogenesis to preferentially elongate anteroposteriorly. Loss of Wnt5, a putative ligand of the planar cell polarity (PCP) pathway, causes the SpM-SHF to expand isotropically. Temporal tracking reveals that the Wnt5a lineage is a unique subpopulation specified as early as E7.5, and undergoes bi-directional deployment to form specifically the pulmonary trunk and the dorsal mesenchymal protrusion (DMP). In Wnt5a −/− mutants, Wnt5a lineage fails to extend into the arterial and venous poles, leading to both outflow tract and atrial septation defects that can be rescued by an activated form of PCP effector Daam1. We identify oriented actomyosin cables in the medial SpM-SHF as a potential Wnt5a-mediated mechanism that promotes SpM-SHF lengthening and restricts its widening. Finally, the Wnt5a lineage also contributes to the pulmonary mesenchyme, suggesting that Wnt5a/PCP is a molecular circuit recruited by the recently identified cardiopulmonary progenitors to coordinate morphogenesis of the pulmonary airways and the cardiac septations necessary for pulmonary circulation. This article has an associated 'The people behind the papers' interview.

A Pictorial Account of Heart Development: Spatial and Temporal Aspects of The Human Embryonic Heart Between 3.5 and 8 Weeks of Development

“…The first wave arises at CS10, and contributes to the cranial wall of the muscular outflow tract until CS14 and to the ascending aorta thereafter. The second wave evolves more gradually between CS11 and CS15, and contributes to the caudal wall of the muscular outflow tract and, after CS14, to the pulmonary trunk 115,116 . These cells of the second wave are dorsally continuous with, and probably originate from a phenotypically similar mass of pharyngeal mesenchyme surrounding the trachea 34,117,118 .…”

“…The progenitor cells in the club converge and extend into a procession of cells that moves towards, and then into the relatively narrow outflow tract before locally differentiating 116,119,120 . Convergent extension is mediated by the planar cell polarity pathway 121 .…”

“…The inner layer of the smooth muscular wall of both arterial trunks derives from the neural crest, and the outer layer from the second heart field. The wall of the ascending aorta is mainly derived from the neural crest 115,131,150 , whereas the wall of the pulmonary trunk originates predominantly in the second heart field 115,116,118,151 . These different contributions may well explain the different growth characteristics of the vessels.…”

Planar cell polarity regulators in asymmetric organogenesis during development and disease

“…Loss of Wnt5a in mice leads to OFT malformations due to impaired cell deployment in the SHF (Sinha et al, 2015). Moreover, Wnt5a functions through Daam1 in OFT morphogenesis by promoting the AP elongation of the SHF (Li et al, 2019).…”

Muscularization of the Mesenchymal Outlet Septum during Cardiac Development

“…Muscularization of the DMP was initially considered to take place by myocardialization [ 29 , 30 , 77 ]. However, more recent work from us and others shows that the DMP becomes muscularized as a result of a mesenchymal-to-myocardial differentiation of SHF-derived mesenchyme [ 75 , 78 , 79 , 80 , 81 , 82 ].…”