Biology subjects

Corrigan, E. K.

Publications and source records attributed to Corrigan, E. K..

4 recordsLinked to original sources

bioRxiv2024

Interspecies Organoids Reveal Human-Specific Molecular Features of Dopaminergic Neuron Development and Vulnerability

The disproportionate expansion of telencephalic structures during human evolution involved tradeoffs that imposed greater connectivity and metabolic demands on midbrain dopaminergic neurons. Despite the central role of dopaminergic neurons in human-enriched disorders, molecular specializations associated with human-specific features and vulnerabilities of the dopaminergic system remain unexplored. Here, we establish a phylogeny-in-a-dish approach to examine gene regulatory evolution by differentiating pools of human, chimpanzee, orangutan, and macaque pluripotent stem cells into ventral midbrain organoids capable of forming long-range projections, spontaneous activity, and dopamine release. We identify human-specific gene expression changes related to axonal transport of mitochondria and reactive oxygen species buffering and candidate cis- and trans-regulatory mechanisms underlying gene expression divergence. Our findings are consistent with a model of evolved neuroprotection in response to tradeoffs related to brain expansion and could contribute to the discovery of therapeutic targets and strategies for treating disorders involving the dopaminergic system.

evolutionary biology↗

bioRxiv2024

Conservation, alteration, and redistribution of mammalian striatal interneurons

Mammalian brains vary in size, structure, and function, but the extent to which evolutionarily novel cell types contribute to this variation remains unresolved1-4. Recent studies suggest there is a primate-specific population of striatal inhibitory interneurons, the TAC3 interneurons5. However, there has not yet been a detailed analysis of the spatial and phylogenetic distribution of this population. Here, we profile single cell gene expression in the developing pig (an ungulate) and ferret (a carnivore), representing 94 million years divergence from primates, and assign newborn inhibitory neurons to initial classes first specified during development6. We find that the initial class of TAC3 interneurons represents an ancestral striatal population that is also deployed towards the cortex in pig and ferret. In adult mouse, we uncover a rare population expressing Tac2, the ortholog of TAC3, in ventromedial striatum, prompting a reexamination of developing mouse striatal interneuron initial classes by targeted enrichment of their precursors. We conclude that the TAC3 interneuron initial class is conserved across Boreoeutherian mammals, with the mouse population representing Th striatal interneurons, a subset of which expresses Tac2. This study suggests that initial classes of telencephalic inhibitory neurons are largely conserved and that during evolution, neuronal types in the mammalian brain change through redistribution and fate refinement, rather than by derivation of novel precursors early in development.

evolutionary biology↗

bioRxiv2024

A pluripotent stem cell platform for in vitro systems genetics studies of mouse development

The directed differentiation of pluripotent stem cells (PSCs) from panels of genetically diverse individuals is emerging as a powerful experimental system for characterizing the impact of natural genetic variation on developing cell types and tissues. Here, we establish new PSC lines and experimental approaches for modeling embryonic development in a genetically diverse, outbred mouse stock (Diversity Outbred mice). We show that a range of inbred and outbred PSC lines can be stably maintained in the primed pluripotent state (epiblast stem cells -- EpiSCs) and establish the contribution of genetic variation to phenotypic differences in gene regulation and directed differentiation. Using pooled in vitro fertilization, we generate and characterize a genetic reference panel of Diversity Outbred PSCs (n = 230). Finally, we demonstrate the feasibility of pooled culture of Diversity Outbred EpiSCs as "cell villages", which can facilitate the differentiation of large numbers of EpiSC lines for forward genetic screens. These data can complement and inform similar efforts within the stem cell biology and human genetics communities to model the impact of natural genetic variation on phenotypic variation and disease-risk.

developmental biology↗

bioRxiv2021

Rapid and robust directed differentiation of mouse epiblast stem cells into definitive endoderm and forebrain organoids

Directed differentiation of pluripotent stem cells (PSCs) is a powerful model system for deconstructing embryonic development. Although mice are the most advanced mammalian model system for genetic studies of embryonic development, state-of-the-art protocols for directed differentiation of mouse PSCs into defined lineages require additional steps and generate target cell types with lower purity than analogous protocols for human PSCs, limiting their application as models for mechanistic studies of development. Here, we examine the potential of mouse epiblast stem cells (EpiSCs) cultured in media containing Wnt pathway inhibitors as a starting point for directed differentiation. As a proof-of-concept, we focused our efforts on two specific cell/tissue types that have proven difficult to generate efficiently and reproducibly from mouse embryonic stem cells: definitive endoderm and neural organoids. We present new protocols for rapid generation of nearly pure definitive endoderm and forebrain-patterned neural organoids that model the development of prethalamic and hippocampal neurons. These differentiation models present new possibilities for combining mouse genetic tools with in vitro differentiation to characterize molecular and cellular mechanisms of embryonic development. SUMMARY STATEMENTNew optimized protocols for directed differentiation of mouse epiblast stem cells into definitive endoderm and forebrain-patterned organoids.

developmental biology↗