cdonandbocaffect trunk neural crest cell migration non-cell autonomously through a reduction of hedgehog signaling in zebrafish slow-twitch muscle

Abstract

The immunoglobin superfamily members cdon and boc are transmembrane proteins implicated in regulating hedgehog signaling during vertebrate development. Recent work showing roles for these genes in axon guidance and neural crest cell migration further suggest that cdon/boc may play additional functions in regulating directed cell movements during development. Here we use novel and existing mutants to investigate a role for cdon and boc in zebrafish neural crest cell migration. We find that single cdon or boc mutant embryos exhibit normal neural crest phenotypes, but that neural crest migration is strikingly disrupted in double cdon/boc mutant embryos. We further show that this neural crest migration phenotype is associated with defects to the differentiation of slow-twitch muscle cells, and that this slow-twitch muscle phenotype is a consequence of reduced hedgehog signaling in mutant fish. While neural crest migratory ability is not affected in double mutant embryos, neural crest directionality is severely affected. These data suggest that neural crest migration defects are likely to be secondary to defects in slow-twitch muscle differentiation. Combined, our data add to a growing literature showing that cdon and boc act synergistically to promote hedgehog signaling during vertebrate development, and provide a foundation for using zebrafish to further study the function of these hedgehog receptor paralogs.

Cdonis required for organ Left-Right patterning via regulating DFCs migration and the sequential ciliogenesis

“…The role of Cdon in organ development and function had been reported in many literatures, including the role in neural differentiation, migration and survival (Jeong et al, 2014;Kim et al, 2023;Powell et al, 2015;Uluca et al, 2022;Wang et al, 2017), cardiac remodeling and fibrosis (Jeong et al, 2017) and myoblast fusion (Castiglioni et al, 2018). More recently, in zebrafish cdon was reported being involved in trunk neural crest cell migration and slow-twitch muscle development (Lencer et al, 2023) and limb growth (Echevarria-Andino et al, 2023). While in more early stage whether it plays a critical role in organ LR patterning is not reported.…”

“…S1). On the other hand, Cdon has also been reported to control cell apoptosis and cell migration in various kinds of cells (Chapouly et al, 2020;Lencer et al, 2023;Sanchez-Arrones et al, 2012). These facts above suggest that cdon may be involved in regulation of clustering movement of DFCs and the sequential organ LR patterning in zebrafish.…”

“…In zebrafish, cdon and boc had been reported to being involved in trunk neural crest cells (NCs) migration and correct proximo-distal patterning in eye development (Jeong et al, 2014;Lencer et al, 2023), demonstrating the crucial role of cdon in zebrafish organ development. Since Cdon and Boc synergistically regulate NCs migration (Lencer et al, 2023), facial and eye development (Zhang et al, 2011), to study the role of cdon in more early embryonic development, we examined the detailed expression pattern of cdon and boc from 128-cell stage to 24hpf. The data showed that cdon is a maternal factor which distributing in cells unequally (Fig.…”

“…Cell-adhension molecule-related/down-regulated by oncogenes (Cdon) and its paralog Boc (Brother of Cdo (Kang et al, 2002)) are two members of cell adhesion molecule subfamily III Ig/fibronectin (Jeong et al, 2014;Sanchez-Arrones et al, 2012), they were reported to synergistically or individually regulate different organs development or disease (Jeong et al, 2014;Jeong et al, 2017;Lencer et al, 2023;Sanchez-Arrones et al, 2012;Zhang et al, 2011). As to Cdon, early reports showed that mouse Cdon regulates skeletal muscle and central nervous system development via Shh and N-cadherin/cell adhesion (Cole et al, 2004;Jeong et al, 2014;Zhang et al, 2006a;Zhang et al, 2006b).…”

“…As to Boc, early reports showed that it plays a role in axon guidance and neuron growth (Connor et al, 2005;Okada et al, 2006). Recently, Lencer et al found that in zebrafish cdon and boc double mutants display trunck neural crest cells (tNCC) migratory defects and loss of slow-twitch muscle, suggesting a non-cell autonomous role of cdon and boc in regulating tNCC migration (Lencer et al, 2023). Although Cdon and Boc were reported to play important roles in many sections in mouse and zebrafish, their roles in early embryonic development are unknown.…”