title: COUP-TFI promotes radial migration and proper morphology of callosal projection neurons by repressing Rnd2 expression.
abstract: During corticogenesis, late-born callosal projection neurons (CPNs) acquire their laminar position through glia-guided radial migration and then undergo final differentiation. However, the mechanisms controlling radial migration and final morphology of CPNs are poorly defined. Here, we show that in COUP-TFI mutant mice CPNs are correctly specified, but are delayed in reaching the cortical plate and have morphological defects during migration. Interestingly, we observed that the rate of neuronal migration to the cortical plate normally follows a low-rostral to high-caudal gradient, similar to that described for COUP-TFI. This gradient is strongly impaired in COUP-TFI(-/-) brains. Moreover, the expression of the Rho-GTPase Rnd2, a modulator of radial migration, is complementary to both these gradients and strongly increases in the absence of COUP-TFI function. We show that COUP-TFI directly represses Rnd2 expression at the post-mitotic level along the rostrocaudal axis of the neocortex. Restoring correct Rnd2 levels in COUP-TFI(-/-) brains cell-autonomously rescues neuron radial migration and morphological transitions. We also observed impairments in axonal elongation and dendritic arborization of COUP-TFI-deficient CPNs, which were rescued by lowering Rnd2 expression levels. Thus, our data demonstrate that COUP-TFI modulates late-born neuron migration and favours proper differentiation of CPNs by finely regulating Rnd2 expression levels.
authors.affiliation: Telethon Institute of Genetics and Medicine (TIGEM), Developmental Disorders Program, 80131 Naples, Italy.
authors.forename: Christian
authors.initials: C
authors.lastname: Alfano
authors.forename: Luigi
authors.initials: L
authors.lastname: Viola
authors.forename: Julian Ik-Tsen
authors.initials: JI
authors.lastname: Heng
authors.forename: Marinella
authors.initials: M
authors.lastname: Pirozzi
authors.forename: Michael
authors.initials: M
authors.lastname: Clarkson
authors.forename: Gemma
authors.initials: G
authors.lastname: Flore
authors.forename: Antonia
authors.initials: A
authors.lastname: De Maio
authors.forename: Andreas
authors.initials: A
authors.lastname: Schedl
authors.forename: François
authors.initials: F
authors.lastname: Guillemot
authors.forename: Michèle
authors.initials: M
authors.lastname: Studer
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism; D051838:COUP Transcription Factor I / Q000235:genetics / Q000378:metabolism*; D002454:Cell Differentiation / Q000502:physiology; D002465:Cell Movement / Q000502:physiology*; D003337:Corpus Callosum / Q000166:cytology* / Q000196:embryology; D005260:Female; D018507:Gene Expression Regulation, Developmental; D051379:Mice; D019579:Neocortex / Q000166:cytology / Q000196:embryology; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D055495:Neurogenesis / Q000502:physiology; D009474:Neurons / Q000166:cytology* / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology; D020741:rho GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D051838:COUP Transcription Factor I; D009419:Nerve Tissue Proteins; D020741:rho GTP-Binding Proteins; C102938:Neurog2 protein, mouse; C475019:Rnd2 protein, mouse