MOST CREATIVE:
Foxp1 and Foxp2 regulate cerebellar hemisphere formation by controlling the diversification of Purkinje cells
Presenter name: Nagham Khouri-Farah, PhD Candidate
Affiliated Lab: Li and Cotney Labs, Department of Genetics and Genome Sciences, UConn Health
Abstract: Purkinje cells (PC) are the sole output neurons of the cerebellar cortex and play a pivotal role in cerebellum functioning. Furthermore, PC are presumed to orchestrate cerebellar development by regulating the differentiation of other cerebellar cell types. In the mammalian cerebellum, PC display transient molecular heterogeneity during development. However, the underpinnings of PC heterogeneity remain poorly understood due to the lack of entry to assess individual PC subtypes. Through single-cell RNA sequencing, we identified 11 molecularly distinct PC subtypes in the embryonic mouse cerebellum. Using CyCIF, a highly multiplexed immunofluorescence imaging method, and light-sheet fluorescent microscopy (LSFM), we assigned PC subtypes to their positions and resolved their three-dimensional distribution in the cerebellar cortex. Different subtypes of PCs form distinct cell clusters coinciding with the anteroposterior and mediolateral patterning of the developing cerebellum. Remarkably, PC subtypes display distinctive combinatorial expression patterns of Foxp1 and Foxp2, which have been implicated in developmental speech and language disorders and Autism in humans. Through single-cell genomics and quantitative spatial transcriptomic analysis, we showed that cerebellum-specific deletion of Foxp1 and Foxp2 disrupted a subset of PC subtypes and the formation of the cerebellar hemisphere. Together, our findings demonstrate that Foxp1 and Foxp2 act in concert to govern the differentiation of PC subtypes and, subsequently, control the formation and expansion of the cerebellar hemispheres, which is an innovative feature of the mammalian cerebellum and is involved in higher cognitive functions.
BEST OVERALL:
Novel gene evolution and 3D genome organization
Presenter name: Katherine Fleck, PhD Candidate
Affiliated Lab: Erceg Lab, Department of Molecular and Cell Biology, UConn
Abstract: Genome organization may be intricately tied to regulating genes and associated cell fate decisions. Recent technological advances in mapping of chromosomal interactions and single-cell imaging have provided insights into chromatin organization at various levels including domains, loops, and boundaries. However, how the placements of genes of different evolutionary age in the 3D genome landscape relate to their biological role remains unclear. In this study, we examine the positioning and functional associations of human genes, grouped by their evolutionary age, within the 3D genomeorganization. We reveal that genes of different evolutionary origin have variable positioning relationships with both domains and loop anchors, but remarkably consistent associations with boundaries across cell types. The functional associations of each grouping of genes are primarily cell type-specific, however, those with recently evolved genes are sensitive to 3D genome architecture. Moreover, the sensitivity of such recent genes in diseased state is more pronounced in loop anchors compared to domains. We complement these findings with analysis of the expression from genes of differing evolutionary ages across cell types. Altogether, these distinct relationships between gene evolutionary age, their function, and positioning within 3D genomic features may contribute to understanding tissue-specific gene regulation in development and disease.