DIS3L2 is essential for neural crest survival by modulating Akt signaling

Abstract

DIS3 like 3-5 exoribonuclease 2 (DIS3L2), an exoribonuclease is known to preferentially degrade uridylated RNA substrates, miRNAs, and ncRNAs. Recent reports show that DIS3L2 also plays a key role in cell proliferation and tumor growth. Mutations in DIS3L2 are associated with congenital disorders such as Perlman syndrome, yet the developmental functions of DIS3L2 remain unknown. We report the developmental role of dis3l2 in neural crest specification, patterning, and survival in the zebrafish embryo. Dis3l2 morphants exhibited reduced expression of neural crest specifier genes coupled with extensive apoptosis in the neural tissue. Our study demonstrates that DIS3L2 regulates neuronal apoptosis and progenitor functions through the Akt -GSK3{beta} signaling pathway. Additionally, we show that DIS3L2 is essential for early mitoses in the zebrafish blastula and plays a key role in maintaining spindle length at metaphase, chromosome congression, spindle pole integrity, and cytokinesis. In summary, we identify new functions of exoribonuclease DIS3L2 in cell fate specification, neural progenitor survival, and mitosis during embryogenesis which form the underlying basis of DIS3L2-associated overgrowth Perlman syndrome. Plain English summaryDIS3 like 3-5 exoribonuclease 2 (DIS3L2) degrades mRNAs and various RNA substrates in the eukaryotic cells. DIS3L2 mutations are associated with congenital overgrowth syndromes like Perlman syndrome and Wilms tumor. The role of DIS3L2 in regulating the embryonic processes remains poorly understood. Our study delineates the developmental functions of DIS3L2 in cell fate determination, survival, and proliferation during vertebrate embryogenesis using zebrafish embryos as a model. We show that DIS3L2 plays a key role in neural crest survival and patterning by modulating Akt-GSK{beta} signaling. We also report unique molecular functions of DIS3L2 in mitotic fidelity and cytokinesis during embryonic mitoses. Our study provides novel insights into the molecular functions of DIS3L2 in regulating neuronal apoptosis during embryonic brain morphogenesis and associated CNS disorders.