Abstract
Forebrain precursor cells are dynamic during early brain development, yet the underlying molecular changes remain elusive. We observed major differences in transcriptional signatures of precursor cells from mouse forebrain at embryonic days E8.5 vs. E10.5 (before vs. after neural tube closure). Genes encoding protein biosynthetic machinery were strongly downregulated at E10.5. This was matched by decreases in ribosome biogenesis and protein synthesis, together with age-related changes in proteomic content of the adjacent fluids. Notably, c-MYC expression and mTOR pathway signaling were also decreased at E10.5, providing potential drivers for the effects on ribosome biogenesis and protein synthesis. Interference with c-MYC at E8.5 prematurely decreased ribosome biogenesis, while persistent c-MYC expression in cortical progenitors increased transcription of protein biosynthetic machinery and enhanced ribosome biogenesis, as well as enhanced progenitor proliferation leading to subsequent macrocephaly. These findings indicate large, coordinated changes in molecular machinery of forebrain precursors during early brain development.
Highlights
Neural tube closure is a fundamental milestone of early brain development, yet relatively little is known about the cellular and molecular transitions occurring in neural precursor cells before and after this process due to experimental challenges inherent to investigating this nascent organ (Greene and Copp, 2014; Massarwa and Niswander, 2013; Wallingford et al, 2013; Wilde et al, 2014)
Some secreted factors (e.g. BMP1 and SHH) were enriched in both E10.5 progenitors and cerebrospinal fluid (CSF), suggesting their secretion into the adjacent fluid (Supplementary file 1; Chau et al, 2015), while factors known to be involved in organismal development and neural tube closure including Wnt5a and Pax3 were enriched in E8.5 (Supplementary file 1)
This work (1) demonstrates that enhanced biogenesis of ribosomes and protein synthetic machinery serve as transcriptional and cell biological signatures defining early forebrain precursor cells; (2) reveals that the changing proteomes of amniotic fluid (AF) and CSF provide a biomarker signature that matches the concurrent, normal development of the adjacent forebrain; (3) identifies MYC as a contributor to the regulation of ribosome biogenesis in the developing forebrain; and (4) shows that persistent MYC expression leads to increased ribosome biogenesis, enhanced cortical progenitor proliferation, and macrocephaly
Summary
Neural tube closure (neurulation) is a fundamental milestone of early brain development, yet relatively little is known about the cellular and molecular transitions occurring in neural precursor cells before and after this process due to experimental challenges inherent to investigating this nascent organ (Greene and Copp, 2014; Massarwa and Niswander, 2013; Wallingford et al, 2013; Wilde et al, 2014). These neurectodermal precursors become progressively lineage restricted as neuroepithelial cells, and radial glial cells, giving rise to all neurons and glia in the adult forebrain (Bjornsson et al, 2015). As these progenitors proliferate, their spatial patterning serves as a blueprint for the maturing brain (Rallu et al, 2002; Sur and Rubenstein, 2005). High expression of the protein biosynthetic machinery together with elevated protein synthesis emerged as a signature of early neural precursors These transcriptional and cell biological changes closely mirrored proteomic changes in the adjacent AF and CSF. Our data identify regulation of protein biosynthetic machinery as an important signature of early forebrain development
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