Ednrb is specifically required to develop neural crest (NC) stem cell-derived lineages. However, it is still unknown why Ednrb signaling is only needed for the early development of melanoblasts in the skin and eye. We show that Ednrb is required for the proliferation of melanoblasts during early mouse development. To understand the mechanism of melanoblast proliferation, we found that the gene absent in melanoma 2 (Aim2) is upregulated in Ednrb-deficient NC cells by RNA-sequencing analysis. Consequently, the knockdown or knockout of Aim2 partially rescued the proliferation of Ednrb-deficient melanoblasts. Conversely, the overexpression of Aim2 in melanoblasts suppressed their proliferation. We further show that Ednrb signaling could act through the microRNA miR-196b to block the suppression of melanoblast proliferation by Aim2 in primary NC cell cultures. These results reveal the Ednrb–Aim2–AKT axis in regulating melanocyte development and suggest that Ednrb signaling functions as a negative regulator of Aim2, which inhibits the proliferation of melanoblasts in early development. These findings uncover a previously unreported role for Aim2 outside the inflammasome, showing that it is a significant regulator controlling NC stem cell-derived lineage development.

Author contributions

Conceptualization: Y.C., L.H.; Methodology: Y.C., H.L., J.W., L.H.; Validation: Y.C., L.H.; Formal analysis: Y.C., H.L., J.W., L.H.; Investigation: Y.C., H.L., J.W., S.Y., Z.S., W.W., C.R.; Resources: Z.S., L.H.; Data curation: Y.C., H.L., J.W., L.H.; Writing - original draft: Y.C., H.L., L.H.; Writing - review & editing: L.H.; Supervision: L.H.; Project administration: Y.C., L.H.; Funding acquisition: Z.S., L.H.

Funding

We gratefully acknowledge the National Natural Science Foundation of China (82070984, 82371081, 30771149), the Natural Science Foundation of Zhejiang Province (LY19C120001), and the Research Development Grant of Wenzhou Medical University for generous funding.

Data availability

Raw RNA-seq data have been deposited to the Gene Expression Omnibus under the accession number GSE275956.

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