Temporal control of progenitor competence shapes maturation in GABAergic neuron development in mice

Inhibitory neurons of the telencephalon are generated from progenitors in the ganglionic eminences that mature and differentiate into specialized cell types. Here, we used scRNA-seq and scATAC-seq together with lineage tracing and birthdating techniques to investigate the influence of neurogenesis timing on the development of GABAergic precursors. We found that the timing of neurogenesis substantially influences the progenitors' maturation competence (the capacity to develop toward a fully functional state), but not their differentiation competence (the ability to evolve into transcriptomically diverse states). The underlying mechanism was chromatin priming, orchestrated by the transcription factor Nfib in collaboration with regulators of inhibitory neuron development. Finally, the heterochronic transplantation of progenitors revealed an interplay between both intrinsic and extrinsic cues acting upon maturation competence. These findings identify a mechanism that coordinates inhibitory neuron development by changing their maturation to achieve maximum adaptability. Transcriptomic,barcode-lineage tracing and Chromatin accessibility of developing mouse forebrain cell subtypes端脑的抑制性神经元源自神经节隆起的祖细胞，此类祖细胞可进一步成熟并分化为特化细胞类型。本研究采用单细胞RNA测序（scRNA-seq）、单细胞转座酶可及性测序（scATAC-seq），结合谱系追踪（lineage tracing）与出生时间标记技术，探究了神经发生时序对GABA能前体细胞发育的影响。研究发现，神经发生时序可显著影响祖细胞的成熟能力（即发育为完全功能状态的潜能），但对其分化能力（即演变为转录组多样化细胞状态的能力）并无显著调控作用。其核心机制为染色质预激活（chromatin priming），由转录因子Nfib与抑制性神经元发育调控因子协同介导。最后，通过祖细胞的异时移植（heterochronic transplantation）实验，本研究揭示了内在与外在信号共同作用于成熟能力的相互关联。上述研究明确了一种通过调节神经元成熟程度以实现最大适应性的调控机制，进而协调抑制性神经元的发育过程。本数据集涵盖发育中小鼠前脑细胞亚型的转录组数据、条形码谱系追踪数据及染色质可及性数据。