Altered temporal sequence of transcriptional regulators in the generation of human cerebellar granule cells

eLife

Thomas S Carroll¹  Arif Kocabas²  David E Buchholz²  Hourinaz Behesti²  Mary E Hatten² 

[1] Bioinformatics Resource Center, Rockefeller University, New York, United States;Laboratory of Developmental Neurobiology, Rockefeller University, New York, United States;

关键词: human pluripotent stem cells;    molecular profiling;    human cerebellum;    cerebellar granule cells;    developmental timing;    quiescent cells;    Human;    Mouse;   

DOI  :  10.7554/eLife.67074

来源: eLife Sciences Publications, Ltd

【 摘 要 】

Brain development is regulated by conserved transcriptional programs across species, but little is known about the divergent mechanisms that create species-specific characteristics. Among brain regions, human cerebellar histogenesis differs in complexity compared with nonhuman primates and rodents, making it important to develop methods to generate human cerebellar neurons that closely resemble those in the developing human cerebellum. We report a rapid protocol for the derivation of the human ATOH1 lineage, the precursor of excitatory cerebellar neurons, from human pluripotent stem cells (hPSCs). Upon transplantation into juvenile mice, hPSC-derived cerebellar granule cells migrated along glial fibers and integrated into the cerebellar cortex. By Translational Ribosome Affinity Purification-seq, we identified an unexpected temporal shift in the expression of RBFOX3 (NeuN) and NEUROD1, which are classically associated with differentiated neurons, in the human outer external granule layer. This molecular divergence may enable the protracted development of the human cerebellum compared to mice.

【 授权许可】

CC BY