The cerebral cortex contains multiple areas with distinctive cytoarchitectonical patterns, but the cellular mechanisms underlying the emergence of this diversity remain unclear. Here, we have investigated the neuronal output of individual progenitor cells in the developing mouse neocortex using a combination of methods that together circumvent the biases and limitations of individual approaches. Our experimental results indicate that progenitor cells generate pyramidal cell lineages with a wide range of sizes and laminar configurations. Mathematical modelling indicates that these outcomes are compatible with a stochastic model of cortical neurogenesis in which progenitor cells undergo a series of probabilistic decisions that lead to the specification of very heterogeneous progenies. Our findings support a mechanism for cortical neurogenesis whose flexibility would make it capable to generate the diverse cytoarchitectures that characterize distinct neocortical areas.
All data generated or analysed during this study are included in the manuscript and supporting files.
- Oscar Marin
- Simon Hippenmeyer
- Fong Kuan Wong
- Fong Kuan Wong
- Robert Beattie
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Animal experimentation: All procedures were approved by King's College London and IST Austria, and were performed under UK Home Office project licenses, and in accordance with Austrian Federal Ministry of Science and Research license, and European regulations (EU directive 86/609, EU decree 2001- 486).
- Sonia Garel, Ecole Normale Superieure, France
© 2019, Llorca et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
Embryonic diapause is a reproductive strategy in which embryo development and growth is temporarily arrested within the uterus to ensure the survival of neonates and mothers during unfavorable conditions. Pregnancy is reinitiated when conditions become favorable for neonatal survival. The mechanism of how the uterus enters diapause in various species remains unclear. Mice with uterine depletion of Foxa2, a transcription factor, are infertile. In this study, we show that dormant blastocysts are recovered from these mice on day 8 of pregnancy with persistent expression of uterine Msx1, a gene critical to maintaining the uterine quiescent state, suggesting that these mice enter embryonic diapause. Leukemia inhibitory factor (LIF) can resume implantation in these mice. Although estrogen is critical for implantation in progesterone-primed uterus, our current model reveals that FOXA2-independent estrogenic effects are detrimental to sustaining uterine quiescence. Interestingly, progesterone and anti-estrogen can prolong uterine quiescence in the absence of FOXA2. Although we find that Msx1 expression persists in the uterus deficient in Foxa2, the complex relationship of FOXA2 with Msx genes and estrogen receptors remains to be explored.
Maternally synthesized products play critical roles in the development of offspring. A premier example is the Caenorhabditis elegans H3K36 methyltransferase MES-4, which is essential for germline survival and development in offspring. How maternal MES-4 protects the germline is not well understood, but its role in H3K36 methylation hinted that it may regulate gene expression in primordial germ cells (PGCs). We tested this hypothesis by profiling transcripts from nascent germlines (PGCs and their descendants) dissected from wild-type and mes-4 mutant (lacking maternal and zygotic MES-4) larvae. mes-4 nascent germlines displayed downregulation of some germline genes, upregulation of some somatic genes, and dramatic upregulation of hundreds of genes on the X chromosome. We demonstrated that upregulation of one or more genes on the X is the cause of germline death by generating and analyzing mes-4 mutants that inherited different endowments of X chromosome(s). Intriguingly, removal of the THAP transcription factor LIN-15B from mes-4 mutants reduced X misexpression and prevented germline death. lin-15B is X-linked and misexpressed in mes-4 PGCs, identifying it as a critical target for MES-4 repression. The above findings extend to the H3K27 methyltransferase MES-2/3/6, the C. elegans version of polycomb repressive complex 2. We propose that maternal MES-4 and PRC2 cooperate to protect germline survival by preventing synthesis of germline-toxic products encoded by genes on the X chromosome, including the key transcription factor LIN-15B.