Abstract
During gastrulation, neural crest cells are specified at the neural plate border, as characterized by Pax7 expression. Using single-cell RNA sequencing coupled with high-resolution in situ hybridization to identify novel transcriptional regulators, we show that chromatin remodeler Hmga1 is highly expressed prior to specification and maintained in migrating chick neural crest cells. Temporally controlled CRISPR-Cas9-mediated knockouts uncovered two distinct functions of Hmga1 in neural crest development. At the neural plate border, Hmga1 regulates Pax7-dependent neural crest lineage specification. At premigratory stages, a second role manifests where Hmga1 loss reduces cranial crest emigration from the dorsal neural tube independent of Pax7. Interestingly, this is rescued by stabilized ß-catenin, thus implicating Hmga1 as a canonical Wnt activator. Together, our results show that Hmga1 functions in a bimodal manner during neural crest development to regulate specification at the neural plate border, and subsequent emigration from the neural tube via canonical Wnt signaling.
Highlights
The neural crest is a vertebrate-specific stem cell population with the capacity to migrate long distances during embryonic development (Bronner and LeDouarin, 2012; Le Douarin, 1980; SimoesCosta and Bronner, 2013)
These results identify a dual role for Hmga1 in neural crest development with an early effect on neural crest specification and a later effect on initiation of migration via the canonical Wnt signaling pathway, mechanisms that may be inappropriately redeployed during tumorigenesis
Our results suggest that Hmga1 mediates the process of EMT by activating canonical Wnt signaling in premigratory neural crest cells, enabling them to emigrate from the neural tube
Summary
The neural crest is a vertebrate-specific stem cell population with the capacity to migrate long distances during embryonic development (Bronner and LeDouarin, 2012; Le Douarin, 1980; SimoesCosta and Bronner, 2013). New tools like single-cell RNA sequencing (scRNA-seq) and Assay for Transposase-Accessible Chromatin using sequencing (ATACseq) have enabled analysis of the neural crest GRN at a global level, helping to clarify lineage trajectories and elucidate key biological processes therein, ranging from proliferation to differentiation (Williams et al, 2019). These approaches have opened the way to extensive functional analysis of important nodes within the GRN, at early stages of neural crest development, which are less well-studied
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