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Mouse and human share conserved transcriptional programs for interneuron development

Updated: 2021-12-10

The general organization and cellular architecture of the telencephalon are conserved among mammals, but its size and complexity vary enormously between rodents and primates. The cerebral cortex contains two main classes of neuron which derive from distinct structures in the developing telencephalon. Excitatory cortical neurons originate from progenitor cells in the developing pallium, whereas GABAergic neurons are generated in the ganglionic eminences, the transitory structures of the fetal brain which also give rise to the basal ganglia. Although we have made substantial progress in elucidating the development of excitatory neurons in the human cortex, our understanding of the generation of GABAergic neurons in the medial, lateral, and caudal ganglionic eminences (MGE, LGE and CGE, respectively) is very limited.


On Dec 10, 2021, a research paper leaded by Prof. WANG Xiaoqun at the Institute of Biophysics, Chinese Academy of Sciences, Prof. Wu Qian at Beijing Normal University and Prof. Oscar Marín at King's College London, entitled " Mouse and human share conserence programs for the interneuron development" was published online in Science. In this study, the researchers systematically characterized the emergence of cell diversity in the human ganglionic eminences from the late first to the early second trimester of human development, which are the transitory structures of the human fetal brain where striatal and cortical GABAergic neurons are generated. They found that these cells are specified within the human ganglionic eminences by transcriptional programs similar to those previously identified in rodents. These findings reveal an evolutionarily conserved regulatory logic controlling the specification, migration, and differentiation of GABAergic neurons in the human telencephalon.


In this study, the researchers identified the molecular features that characterize neural progenitor cells in the human ganglionic eminences. They found that the massive growth of the subventricular zone in the human ganglionic eminences during the second trimester is primarily supported by a large expansion of intermediate progenitor cells. They also revealed the molecular mechanisms underlying the regional specification of progenitor cells as well as the genetic programs driving divergent developmental trajectories in the MGE, LGE, and CGE. In particular, the researchers systematically delineated the developmental trajectories of olfactory bulb neurons, striatal and pallidal GABAergic projection neurons, striatal and cortical GABAergic interneurons, and cholinergic neurons.


Then, the researchers also investigated the developmental mechanisms underlying the emergence of interneuron diversity in the adult human neocortex. Despite the protracted development of human cortical interneurons, the researchers found that the cortical interneuron diversity in human brain is early specified within the ganglionic eminences, long before these cells reach the developing cortex.


Finally, the researchers identified two populations of human interneurons with features that do not seem to be shared with rodents: a prospective novel sub- type of MGE-derived fast-spiking interneurons and a large population of CGE-derived GABAergic interneurons.


In summary, these findings reveal the molecular hierarchies governing the development of neurons generated in the human ganglionic eminences. These results indicate that gene regulatory networks controlling their specification, migration, and differentiation are evolutionarily conserved in mouse and human. This study will advance our understanding of the regulatory logic underlying human brain development. What's more, considering the involvement of striatal and cortical GABAergic neurons in neurodevelopmental disorders such as autism and schizophrenia, these data should enable linking genetic variation to specific cell types to unravel the origin of neurodevelopmental disorders.


Dr. SHI Yingchao, WANG Mengdi and Dr. MI Da are the first authors. This work was supported by grants from the National Key Research and Development Program of China, the Strategic Priority Research Program of the Chinese Academy of Sciences and the National Natural Science Foundation of China.

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Contact: WANG Xiaoqun

Institute of Biophysics, Chinese Academy of Sciences

Beijing 100101, China

Email: xiaoqunwang@ibp.ac.cn


(Reported by Dr. WANG Xiaoqun's group)


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