Molecular Regulation of Gliogenesis in Xenopus Laevis during Primary Neurogenesis



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Glia play essential roles in the vertebrate nervous system. In adults, glia can become mis-regulated, leading to the formation of tumors, including gliomas and glioblastoma (GBM). Understanding glial development is integral to elucidating the mechanisms responsible for the formation and progression of GBM. However, the signals required for initiation of glial development have yet to be completely characterized. Our preliminary studies in Xenopus laevis indicate that glial specification is initiated between Nieuwkoop and Faber (NF) stages 16-18 in the anterior spinal cord. Glial specification progresses posteriorly down the neural tube, occurring anterior of the midbrain-hindbrain boundary only at NF stage 24. Gene expression analysis on isolated explants consisting of either mid-gastrula neural ectoderm or animal cap ectoderm overexpressing the BMP inhibitor Noggin demonstrated that neural plates transcribed glial associated genes at levels akin to those of their whole embryo siblings. In contrast, the expression of glial genes in Noggin-injected animal caps (NogAC), such as olig3, sox10, glast, and glt-1, was significantly reduced. These findings suggest that (1) inhibition of BMP signaling alone is insufficient to induce gliogenesis; and (2) signals from the dorsal mesoderm during gastrulation are required for the initiation of gliogenesis at later stages. Pair-wise comparisons between the transcriptomes of mid-gastrula (NF Stage 11) and mid-neurulation (NF Stage 18) neural plates and NogACs elucidated underlying differences accounting for their distinct developmental potentials. Functional annotation of the differentially expressed genes revealed that glial transcription factors such as pou3f2, sox9, sox10, olig3, and rfx4 and members of Wnt, FGF, and RA signaling pathways were differentially expressed in neural plates. Pharmacological inhibition of these signaling pathways in neural plates suggested distinct functions in glial differentiation. Ectopic expression of TAZ, the master regulator of mesenchymal differentiation in GBM, in X. laevis embryos encouraged persistence of an undifferentiated neural progenitor population, and potentially inhibited glial specification. Our results indicate that signals important for gliogenesis are active in the Xenopus embryos as early as mid-gastrulation and have direct implications in further GBM research.



Glial Development