Why the study?
Purkinje fibers share common progenitors with contractile cardiomyocytes, but the mechanisms of lineage segregation and network morphogenesis are poorly understood.
Nkx2-5 dosage is critical for the proper morphogenesis and cell fate divergence of the cardiac Purkinje fiber network during embryonic development.
Provides mechanistic insight into congenital conduction abnormalities; extends understanding of embryonic Purkinje network development but leaves open.
The ventricular conduction system coordinates heartbeats by rapid propagation of electrical activity through the Purkinje fiber (PF) network. PFs share common progenitors with contractile cardiomyocytes, yet the mechanisms of segregation and network morphogenesis are poorly understood. Here, we apply genetic fate mapping and temporal clonal analysis to identify murine cardiomyocytes committed to the PF lineage as early as E7.5. We find that a polyclonal PF network emerges by progressive recruitment of conductive precursors to this scaffold from a pool of bipotent progenitors. At late fetal stages, the segregation of conductive cells increases during a phase of rapid recruitment to build the definitive PF network through a non-cell autonomous mechanism. We also show that PF differentiation is impaired in Nkx2-5 haploinsufficient embryos leading to failure to extend the scaffold. In particular, late fetal recruitment fails, resulting in PF hypoplasia and persistence of bipotent progenitors. Our results identify how transcription factor dosage regulates cell fate divergence during distinct phases of PF network morphogenesis.
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Choquet et al. (2020) studied this question.
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