Transcriptomic atlas of midbrain dopamine neurons uncovers differential vulnerability in a Parkinsonism lesion model.

Midbrain dopamine (mDA) neurons comprise diverse cells with unique innervation targets and functions. This is illustrated by the selective sensitivity of mDA neurons of the substantia nigra compacta (SNc) in patients with Parkinson's disease, while those in the ventral tegmental area (VTA) are relatively spared. Here, we used single nuclei RNA sequencing (snRNA-seq) of approximately 70,000 mouse midbrain cells to build a high-resolution atlas of mouse mDA neuron diversity at the molecular level.

PRC2-mediated repression is essential to maintain identity and function of differentiated dopaminergic and serotonergic neurons.

How neurons can maintain cellular identity over an entire life span remains largely unknown. Here, we show that maintenance of identity in differentiated dopaminergic and serotonergic neurons is critically reliant on the Polycomb repressive complex 2 (PRC2). Deletion of the obligate PRC2 component, , in these neurons resulted in global loss of H3K27me3, followed by a gradual activation of genes harboring both H3K27me3 and H3K9me3 modifications.

Selective requirement for polycomb repressor complex 2 in the generation of specific hypothalamic neuronal subtypes.

The hypothalamus displays staggering cellular diversity, chiefly established during embryogenesis by the interplay of several signalling pathways and a battery of transcription factors. However, the contribution of epigenetic cues to hypothalamus development remains unclear. We mutated the polycomb repressor complex 2 gene Eed in the developing mouse hypothalamus, which resulted in the loss of H3K27me3, a fundamental epigenetic repressor mark.

Variational autoencoding of gene landscapes during mouse CNS development uncovers layered roles of Polycomb Repressor Complex 2.

A prominent aspect of most, if not all, central nervous systems (CNSs) is that anterior regions (brain) are larger than posterior ones (spinal cord). Studies in Drosophila and mouse have revealed that Polycomb Repressor Complex 2 (PRC2), a protein complex responsible for applying key repressive histone modifications, acts by several mechanisms to promote anterior CNS expansion. However, it is unclear what the full spectrum of PRC2 action is during embryonic CNS development and how PRC2 intersects with the epigenetic landscape.

Genetic mechanisms controlling anterior expansion of the central nervous system.

In bilaterally-symmetric animals (Bilateria), condensation of neurons and ganglia into a centralized nervous system (CNS) constitutes a salient feature. In most, if not all, Bilateria another prominent aspect is that the anterior regions of the CNS are typically larger than the posterior ones. Detailed studies in Drosophila melanogaster (Drosophila) have revealed that anterior expansion in this species stems from three major developmental features: the generation of more progenitors anteriorly, an extended phase of proliferation of anterior progenitors, and more proliferative daughter cells in anterior regions.

Anterior CNS expansion driven by brain transcription factors.

During CNS development, there is prominent expansion of the anterior region, the brain. In , anterior CNS expansion emerges from three rostral features: (1) increased progenitor cell generation, (2) extended progenitor cell proliferation, (3) more proliferative daughters. We find that (mouse ), () and () are important for brain progenitor generation.

Evolutionarily conserved anterior expansion of the central nervous system promoted by a common PcG-Hox program.

A conserved feature of the central nervous system (CNS) is the prominent expansion of anterior regions (brain) compared with posterior (nerve cord). The cellular and regulatory processes driving anterior CNS expansion are not well understood in any bilaterian species. Here, we address this expansion in and mouse.

Anterior-Posterior Gradient in Neural Stem and Daughter Cell Proliferation Governed by Spatial and Temporal Hox Control.

A readily evident feature of animal central nervous systems (CNSs), apparent in all vertebrates and many invertebrates alike, is its "wedge-like" appearance, with more cells generated in anterior than posterior regions. This wedge could conceivably be established by an antero-posterior (A-P) gradient in the number of neural progenitor cells, their proliferation behaviors, and/or programmed cell death (PCD). However, the contribution of each of these mechanisms, and the underlying genetic programs, are not well understood.