title: Ntf3 acts downstream of Sip1 in cortical postmitotic neurons to control progenitor cell fate through feedback signaling.
abstract: Cortical progenitors undergo progressive fate restriction, thereby sequentially producing the different layers of the neocortex. However, how these progenitors precisely change their fate remains highly debatable. We have previously shown the existence of cortical feedback mechanisms wherein postmitotic neurons signal back to the progenitors and promote a switch from neurogenesis to gliogenesis. We showed that Sip1 (Zeb2), a transcriptional repressor, controls this feedback signaling. A similar mechanism was also suggested to control neuronal cell type specification; however, the underlying mechanism was not identified. Here, we provide direct evidence that in the developing mouse neocortex, Ntf3, a Sip1 target neurotrophin, acts as a feedback signal between postmitotic neurons and progenitors, promoting both apical progenitor (AP) to basal progenitor (BP) and deep layer (DL) to upper layer (UL) cell fate switches. We show that specific overexpression of Ntf3 in neocortical neurons promotes an overproduction of BP at the expense of AP. This shift is followed by a decrease in DL and an increase in UL neuronal production. Loss of Ntf3, by contrast, causes an increase in layer VI neurons but does not rescue the Sip1 mutant phenotype, implying that other parallel pathways also control the timing of progenitor cell fate switch.
authors.affiliation: Institute for Cell and Neurobiology, Center for Anatomy, Charité-Universitätsmedizin Berlin, Berlin 10117, Germany Max Planck Institute for Experimental Medicine, Goettingen 37075, Germany.
authors.forename: Srinivas
authors.initials: S
authors.lastname: Parthasarathy
authors.affiliation: Institute for Cell and Neurobiology, Center for Anatomy, Charité-Universitätsmedizin Berlin, Berlin 10117, Germany Max Planck Institute for Experimental Medicine, Goettingen 37075, Germany.
authors.forename: Swathi
authors.initials: S
authors.lastname: Srivatsa
authors.affiliation: Institute for Cell and Neurobiology, Center for Anatomy, Charité-Universitätsmedizin Berlin, Berlin 10117, Germany.
authors.forename: Anjana
authors.initials: A
authors.lastname: Nityanandam
authors.affiliation: Institute for Cell and Neurobiology, Center for Anatomy, Charité-Universitätsmedizin Berlin, Berlin 10117, Germany victor.tarabykin@charite.de.
authors.forename: Victor
authors.initials: V
authors.lastname: Tarabykin
mesh_terms: D000818:Animals; D002452:Cell Count; D019070:Cell Lineage; D002540:Cerebral Cortex; D004622:Embryo, Mammalian / Q000166:cytology / Q000378:metabolism; D025461:Feedback, Physiological; D005260:Female; D017353:Gene Deletion; D008297:Male; D051379:Mice; D008938:Mitosis; D009030:Mosaicism; D009154:Mutation / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D058953:Neural Stem Cells / Q000166:cytology*; D055495:Neurogenesis; D009474:Neurons / Q000166:cytology*; D020933:Neurotrophin 3 / Q000378:metabolism*; D010641:Phenotype; D015398:Signal Transduction; D015854:Up-Regulation
chemical_list: D009419:Nerve Tissue Proteins; D020933:Neurotrophin 3; C491561:Sip1 protein, mouse
keywords: Cell fate; Cortical development; Feedback signaling; Ntf3; Sip1; Zeb2