Abstract
ABSTRACTThe mechanisms underlying spatial and temporal control of cortical neurogenesis of the brain are largely elusive. Long non-coding RNAs (lncRNAs) have emerged as essential cell fate regulators. Here we found LncKdm2b (also known as Kancr), a lncRNA divergently transcribed from a bidirectional promoter of Kdm2b, is transiently expressed during early differentiation of cortical projection neurons. Interestingly, Kdm2b’s transcription is positively regulated in cis by LncKdm2b, which has intrinsic-activating function and facilitates a permissive chromatin environment at the Kdm2b’s promoter by associating with hnRNPAB. Lineage tracing experiments and phenotypic analyses indicated LncKdm2b and Kdm2b are crucial in proper differentiation and migration of cortical projection neurons. These observations unveiled a lncRNA-dependent machinery in regulating cortical neuronal differentiation.
Highlights
IntroductionProjection neurons (PNs) are the main functional units, expressing excitatory neurotransmitters, with their long axons projecting into subcortical regions or contralateral cortex of the brain
The mammalian cerebral cortex, known as the neocortex, is a six-layered structure and responsible forWei Li and Wenchen Shen contributed to the work.Electronic supplementary material The online version of this article contains supplementary material, which is available to authorized users.performing the most sophisticated cognitive and perceptual functions such as sensory perception, generation of motor commands, conscious thought and language
Since LncKdm2b regulates the expression of lysine-specific demethylase 2B (Kdm2b), and Kdm2b is transiently expressed in freshly born projection neurons, we explored roles and mechanisms of KDM2B in cortical neurogenesis
Summary
Projection neurons (PNs) are the main functional units, expressing excitatory neurotransmitters, with their long axons projecting into subcortical regions or contralateral cortex of the brain. Cortical PNs are largely generated between embryonic (E) day 11.5 to E17.5 indirectly from radial glial progenitor cells (RGPCs), whose nuclei lie in the region close to the lateral ventricles, ventricular zone (VZ). IPCs divide symmetrically to generate either two IPCs or two postmitotic PNs. PNs migrate radially along the basal processes of RGPCs to propagate the cortical plate (CP) in the basal part of the cortex, which eventually forms cortical layers (Fietz and Huttner, 2011; Kwan et al, 2012). Many cellular and molecular aspects governing cortical neurogenesis have been extensively studied, including cell-autonomous and non-autonomous regulation of RGPCs’ asymmetric cell division, neuronal fate commitment, as well as PNs’ radial migration (Ayala et al, 2007; Greig et al, 2013; Imayoshi and Kageyama, 2014). Mechanisms that control the initial numbers and proliferation rates of RGPCs, as well as the proliferative or neurogenic choices of IPCs, are largely elusive (Greig et al, 2013; Homem et al, 2015)
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