A transcription repressor promotes astrocytogenesis during neocortical development
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The mammalian neocortex is a complex and highly organized structure that contains diverse neuronal and glial cell types. In the developing central nervous system (CNS), neurons and two types of glial cells—astrocytes and oligodendrocytes—are generated from common multipotent neural precursor cells (NPCs). NPCs first give rise to neurons at early stages of brain development and subsequently differentiate into glia at later stages. This precise temporal control of NPC fate is crucial for proper development of the CNS.
Astrocytes are the most numerous cell type in the mammalian brain and perform diverse functions such as recycling of neurotransmitters, energy storage, formation of the blood–brain barrier and regulation of synapse formation and function. Astrocytogenesis begins towards the end of the neurogenic period and is regulated by extrinsic signals such as growth factors and cytokines, leukemia inhibitory factor, ciliary neurotrophic factor (CNTF), cardiotrophin-1, bone morphogenetic protein (BMP) as well as by cell-intrinsic programmes such as epigenetic chromatin modification.
The transcription factors Sox9 and nuclear factor I/A (NFIA) are implicated in astrocyte specification in the embryonic spinal cord. However, Sox9 and NFIA do not exclusively mark precursors committed to the astrocytic fate. Authors therefore hypothesized that some other molecule or mechanism essential for astrocyte specification remains to be discovered.
Zinc finger- and BTB domain-containing protein 20 (Zbtb20) is a member of the BTB/POZ family of transcription factors and functions as a transcriptional repressor. Zbtb20 is expressed in developing hippocampal neurons and plays a key role in hippocampal development and function. Although Zbtb20 is expressed in astrocytes in the cerebral cortex and cerebellum, its role in astrocyte development has not been elucidated.
Authors have now identified Zbtb20 as an essential regulator of astrocyte development in the developing mouse CNS. They found that Zbtb20 is highly expressed in NPCs at late stages (during the gliogenic period) of neocortical development, as well as in differentiating and mature astrocytes.
Overexpression and knockdown experiments in vitro and in vivo revealed that Zbtb20 promotes the production of astrocytes and suppresses that of neurons. Given that knockdown of Sox9 or NFIA attenuated the promotion of astrocyte production by Zbtb20, Zbtb20 appears to cooperate with Sox9 and NFIA during astrocyte development.
Moreover, Zbtb20 directly repressed expression of the mouse brain-2 (Brn2) gene, with Brn2 being essential for neocortical neurogenesis. These results suggest that Zbtb20, together with Sox9 and NFIA, promotes astrocytogenesis in part through the repression ofBrn2 expression in the neocortex.http://www.nature.com/ncomms/2016/160322/ncomms11102/full/ncomms11102.html