Cerebellar nuclei evolved by repeatedly duplicating a conserved cell-type set

doi:10.1126/science.abd5059

GSTDTAP > 气候变化

DOI	10.1126/science.abd5059
	Cerebellar nuclei evolved by repeatedly duplicating a conserved cell-type set
	Justus M. Kebschull; Ethan B. Richman; Noam Ringach; Drew Friedmann; Eddy Albarran; Sai Saroja Kolluru; Robert C. Jones; William E. Allen; Ying Wang; Seung Woo Cho; Huaijun Zhou; Jun B. Ding; Howard Y. Chang; Karl Deisseroth; Stephen R. Quake; Liqun Luo
	2020-12-18
发表期刊	Science
出版年	2020
英文摘要	Cerebellar nuclei, substructures of the cerebellum, transfer information from the cerebellum to other parts of the brain. Using single-cell transcriptomics, Kebschull et al. have now identified a conserved pattern of cerebellar nuclei structure that has been repeated through evolution (see the Perspective by Hatten). Ranging from mice to chickens to humans, cerebellar nuclei are made up of region-specific excitatory neurons and region-invariant inhibitory neurons. In humans, a facet connecting the cerebellum to the frontal cortex is enhanced. Science , this issue p. [eabd5059][1]; see also p. [1411][2] ### INTRODUCTION The brains of extant animals have evolved over hundreds of millions of years from simple circuits. Cell types diversified, connections elaborated, and new brain regions emerged. Models for brain region evolution range from duplication of existing regions to splitting of previously multifunctional regions and de novo assembly from existing cell types. These models, however, have not been demonstrated in vertebrate brains at cell-type resolution. ### RATIONALE We investigated brain region evolution using the cerebellar nuclei as a model system. The cerebellum is a major hindbrain structure in jawed vertebrates, comprising the cerebellar cortex and cerebellar nuclei. It is thought to act as a feedforward model for motor control and cognitive processes. The cerebellar cortex receives and processes inputs and sends outputs to the cerebellar nuclei, which route the results of cerebellar computations to the rest of the brain. Whereas the cerebellar cortex is well conserved across vertebrates, the cerebellar nuclei vary in number, with none in jawless vertebrates, one pair in cartilaginous fishes and amphibians, two pairs in reptiles and birds, and three pairs in mammals. This pattern suggests that extant cerebellar nuclei evolved from a single ancestral nucleus. Cerebellar nuclei thus provide a good model to interrogate brain region evolution. ### RESULTS We characterized the cerebellar nuclei in mice, chickens, and humans using whole-brain and spinal cord projection mapping in cleared samples, single-nucleus RNA sequencing (snRNAseq), and spatially resolved transcript amplicon readout mapping (STARmap) analysis. We first compared the projection patterns of the three cerebellar nuclei of mice. Our data reveal broad projections of all nuclei, which in common target regions are shifted relative to each other. To understand the transcriptomic differences that underlie these shifting projections, we produced a cell-type atlas of the mouse cerebellar nuclei using snRNAseq. We discovered three region-invariant inhibitory cell classes and 15 region-specific excitatory cell types. Excitatory cell types fall into two classes with distinct gene expression and electrophysiological properties. Members of each class are present in every nucleus and are putative sister cell types. STARmap analysis in mice revealed that the organizational unit of the cerebellar nuclei is cytoarchitectonically distinguishable subnuclei, each of which contains the three inhibitory and two excitatory classes. To test whether this archetypal subnucleus is also the evolutionary unit of the cerebellar nuclei, we performed snRNAseq and STARmap on the chicken cerebellar nuclei. We identified four subnuclei, three of which had direct orthologs in mice. Each chicken subnucleus contained the same cell-type set of three inhibitory and two excitatory classes already identified in mice, confirming our hypothesis. Cerebellar nuclei vary in size across vertebrates. In particular, the human lateral nucleus is markedly expanded. To understand this expansion, we performed snRNAseq in humans. We found that the medial and interposed nuclei maintained the archetypal cerebellar nuclei composition. However, the lateral nucleus expanded one excitatory cell class at the expense of the other. Conditional tracing in the mouse lateral nucleus revealed that the cell class expanded in humans preferentially accesses lateral frontal cortices via specific intermediate thalamic nuclei. ### CONCLUSION We identified a conserved cell-type set that forms an archetypal cerebellar nucleus as the unit of cerebellar nuclei organization and evolution. We propose that this archetypal nucleus was repeatedly duplicated during evolution, accompanied primarily by transcriptomic divergence of excitatory neurons and shifts in their projection patterns. Our data support a model of duplication-and-divergence of entire cell-type sets for brain region evolution. ![Figure][3] Evolution of the cerebellar nuclei. Comparative single-cell transcriptomics in mice, chickens, and humans (top left; neurons are color-coded by type), spatial transcriptomic analyses in mice and chickens (top right; neurons are color-coded by type in raw and processed data), and central nervous system (CNS)–wide projection mapping in mice (bottom left; axons in red in a three-dimensional mouse brain) revealed the unit of cerebellar nuclei organization and evolution. This unit (red box) comprises three inhibitory and two excitatory neuron classes (each colored circle indicates a neuron class). Extant cerebellar nuclei likely derived from the duplication and divergence of this unit, with more dynamic gene expression in excitatory neurons (changed color hues), along with projection target shifts. How have complex brains evolved from simple circuits? Here we investigated brain region evolution at cell-type resolution in the cerebellar nuclei, the output structures of the cerebellum. Using single-nucleus RNA sequencing in mice, chickens, and humans, as well as STARmap spatial transcriptomic analysis and whole–central nervous system projection tracing, we identified a conserved cell-type set containing two region-specific excitatory neuron classes and three region-invariant inhibitory neuron classes. This set constitutes an archetypal cerebellar nucleus that was repeatedly duplicated to form new regions. The excitatory cell class that preferentially funnels information to lateral frontal cortices in mice becomes predominant in the massively expanded human lateral nucleus. Our data suggest a model of brain region evolution by duplication and divergence of entire cell-type sets. [1]: /lookup/doi/10.1126/science.abd5059 [2]: /lookup/doi/10.1126/science.abf4483 [3]: pending:yes
领域	气候变化 ; 资源环境
URL	查看原文
引用统计
文献类型	期刊论文
条目标识符	http://119.78.100.173/C666/handle/2XK7JSWQ/308357
专题	气候变化资源环境科学
推荐引用方式 GB/T 7714	Justus M. Kebschull,Ethan B. Richman,Noam Ringach,et al. Cerebellar nuclei evolved by repeatedly duplicating a conserved cell-type set[J]. Science,2020.
APA	Justus M. Kebschull.,Ethan B. Richman.,Noam Ringach.,Drew Friedmann.,Eddy Albarran.,...&Liqun Luo.(2020).Cerebellar nuclei evolved by repeatedly duplicating a conserved cell-type set.Science.
MLA	Justus M. Kebschull,et al."Cerebellar nuclei evolved by repeatedly duplicating a conserved cell-type set".Science (2020).