Christophers, B. | bioRxiv Science

bioRxiv2024

Cooperation between Nodal and FGF signals regulates zebrafish cardiac cell migration and heart morphogenesis

Asymmetric development of the vertebrate heart is driven by a complex sequence of morphogenetic cell movements, coordinated through precise interpretation of signaling cues by the heart primordia. Here, we show that Nodal signaling functions synergistically with FGF to stimulate the migration of cardiac progenitor cells (CPCs) during cardiac jogging--the first morphological asymmetry observed in zebrafish heart development. While Nodal directs the asymmetric migration of CPCs, we find FGF signaling to be dispensable for this asymmetry, suggesting that FGF plays a permissive rather than instructive role. We further demonstrate that Nodal signaling induces asymmetries in actin cytoskeletal dynamics that correlate with the directional migration of CPCs, while FGF does not influence this actin asymmetry. In addition to influencing jogging, FGF and Nodal synergize to ensure proper heart looping. We also provide evidence that FGF contributes to heart looping by promoting the differentiation of the second heart field. Together, these findings offer insight into how the spatiotemporal dynamics of signaling pathways regulate the cellular behaviors driving organ morphogenesis. Summary statementThis study explores the synergistic and independent roles of Nodal and FGF signaling in generating heart asymmetry.

developmental biology↗

bioRxiv2023

Muscle cofilin alters neuromuscular junction postsynaptic development to strengthen functional neurotransmission

Cofilin, an actin severing protein, plays critical roles in muscle sarcomere addition and maintenance. Our previous work has shown Drosophila cofilin (DmCFL) knockdown causes progressive deterioration of muscle structure and function and produces features seen in nemaline myopathy (NM) caused by cofilin mutations. We hypothesized that disruption of actin cytoskeleton dynamics by DmCFL knockdown would impact other aspects of muscle development, and, thus, conducted an RNA sequencing analysis which unexpectedly revealed upregulated expression of numerous neuromuscular junction (NMJ) genes. We found that DmCFL is enriched in the muscle postsynaptic compartment and that DmCFL deficiency causes F-actin disorganization in this subcellular domain prior to the sarcomere defects observed later in development. Despite NMJ gene expression changes, we found no significant changes in gross presynaptic Bruchpilot active zones or total postsynaptic glutamate receptor levels. However, DmCFL knockdown results in mislocalization of glutamate receptors containing the GluRIIA subunit in more deteriorated muscles and neurotransmission strength is strongly impaired. These findings expand our understanding of cofilins roles in muscle to include NMJ structural development and suggest that NMJ defects may contribute to NM pathophysiology. Summary statementCofilin regulates muscle postsynaptic actin organization, structural maintenance, glutamate receptor composition, and neuromuscular junction function in a Drosophila nemaline myopathy disease model.

developmental biology↗