Biology subjects

Li, K. X.

Publications and source records attributed to Li, K. X..

3 recordsLinked to original sources

bioRxiv2024

Astrocyte regional specialization is shaped by postnatal development

Astrocytes are an abundant class of glial cells with critical roles in neural circuit assembly and function. Though many studies have uncovered significant molecular distinctions between astrocytes from different brain regions, how this regionalization unfolds over development is not fully understood. We used single-nucleus RNA sequencing to characterize the molecular diversity of brain cells across six developmental stages and four brain regions in the mouse and marmoset brain. Our analysis of over 170,000 single astrocyte nuclei revealed striking regional heterogeneity among astrocytes, particularly between telencephalic and diencephalic regions, at all developmental time points surveyed in both species. At the stages sampled, most of the region patterning was private to astrocytes and not shared with neurons or other glial types. Though astrocytes were already regionally patterned in late embryonic stages, this region-specific astrocyte gene expression signature changed dramatically over postnatal development, and its composition suggests that regional astrocytes further specialize postnatally to support their local neuronal circuits. Across mouse and marmoset, we found hundreds of species differentially expressed genes, as well as divergence in the expression of astrocytic region- and age-differentially expressed genes and the timing of astrocyte maturation relative to birth between the species. Finally, we used expansion microscopy to show that astrocyte morphology is also regionally specialized across cortex, striatum, and thalamus in the mouse.

neuroscience↗

bioRxiv2023

An integrated transcriptomic cell atlas of human neural organoids

Neural tissues generated from human pluripotent stem cells in vitro (known as neural organoids) are becoming useful tools to study human brain development, evolution and disease. The characterization of neural organoids using single-cell genomic methods has revealed a large diversity of neural cell types with molecular signatures similar to those observed in primary human brain tissue. However, it is unclear which domains of the human nervous system are covered by existing protocols. It is also difficult to quantitatively assess variation between protocols and the specific cell states in organoids as compared to primary counterparts. Single-cell transcriptome data from primary tissue and neural organoids derived with guided or un-guided approaches and under diverse conditions combined with large-scale integrative analyses make it now possible to address these challenges. Recent advances in computational methodology enable the generation of integrated atlases across many data sets. Here, we integrated 36 single-cell transcriptomics data sets spanning 26 protocols into one integrated human neural organoid cell atlas (HNOCA) totaling over 1.7 million cells. We harmonize cell type annotations by incorporating reference data sets from the developing human brain. By mapping to the developing human brain reference, we reveal which primary cell states have been generated in vitro, and which are under-represented. We further compare transcriptomic profiles of neuronal populations in organoids to their counterparts in the developing human brain. To support rapid organoid phenotyping and quantitative assessment of new protocols, we provide a programmatic interface to browse the atlas and query new data sets, and showcase the power of the atlas to annotate new query data sets and evaluate new organoid protocols. Taken together, the HNOCA will be useful to assess the fidelity of organoids, characterize perturbed and diseased states and facilitate protocol development in the future.

developmental biology↗

bioRxiv2022

A marmoset brain cell census reveals persistent influence of developmental origin on neurons

The mammalian brain is composed of many brain structures, each with its own ontogenetic and developmental history. Transcriptionally-based cell type taxonomies reveal cell type composition and similarity relationships within and across brain structures. We sampled over 2.4 million brain cells across 18 locations in the common marmoset, a New World monkey primed for genetic engineering, and used single-nucleus RNA sequencing to examine global gene expression patterns of cell types within and across brain structures. Our results indicate that there is generally a high degree of transcriptional similarity between GABAergic and glutamatergic neurons found in the same brain structure, and there are generally few shared molecular features between neurons that utilize the same neurotransmitter but reside in different brain structures. We also show that in many cases the transcriptional identities of cells are intrinsically retained from their birthplaces, even when they migrate beyond their cephalic compartments. Thus, the adult transcriptomic identity of most neuronal types appears to be shaped much more by their developmental identity than by their primary neurotransmitter signaling repertoire. Using quantitative mapping of single molecule FISH (smFISH) for markers for GABAergic interneurons, we found that the similar types (e.g. PVALB+ interneurons) have distinct biodistributions in the striatum and neocortex. Interneuron types follow medio-lateral gradients in striatum but form complex distributions across the neocortex that are not described by simple gradients. Lateral prefrontal areas in marmoset are distinguished by high relative proportions of VIP+ neurons. We further used cell-type-specific enhancer driven AAV-GFP to visualize the morphology of molecularly-resolved interneuron classes in neocortex and striatum, including the previously discovered novel primate-specific TAC3+ striatal interneurons. Our comprehensive analyses highlight how lineage and functional class contribute to the transcriptional identity and biodistribution of primate brain cell types. One-Sentence SummaryAdult primate neurons are imprinted by their region of origin, more so than by their functional identity.

neuroscience↗