Adhesion dynamics in the neocortex determine the start of migration and the post-migratory orientation of neurons

Epifanova, Ekaterina A.; Salina, V. A.; Lajkó, Denis; Textoris-Taube, Kathrin; Naumann, T.; Bormuth, Olga; Bormuth, Ingo; Horan, Stephen T.; Schaub, Thomas; Борисова, Е. В.; Ambrozkiewicz, Mateusz C.; Tarabykin, Victor; Rosário, Marta

doi:10.1126/sciadv.abf1973

Cited by 4 publications

(1 citation statement)

References 64 publications

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“…For example, C3G-Rap1 mediated inside-out activation of α5β1 integrin is required for neuronal migration (Sekine et al, 2012;Shah et al, 2016). However, a more recent study has indicated that that Zeb2mediated downregulation of β1 integrin surface expression may enable timely migration from the subventricular zone (Epifanova et al, 2021). Similarly, elevated expression of β1 integrin and FAK in glia due to deletion of MARVELD1, a novel nuclear protein, also caused aberrant neuronal migration (Liu et al, 2018).…”

Section: Discussionmentioning

confidence: 99%

Delayed cortical development in mice with a neural specific deletion of β1 integrin

Rashid

Olson

2023

Front. Neurosci.

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The adhesion systems employed by migrating cortical neurons are not well understood. Genetic deletion studies of focal adhesion kinase (FAK) and paxillin in mice suggested that these classical focal adhesion molecules control the morphology and speed of cortical neuron migration, but whether β1 integrins also regulate migration morphology and speed is not known. We hypothesized that a β1 integrin adhesion complex is required for proper neuronal migration and for proper cortical development. To test this, we have specifically deleted β1 integrin from postmitotic migrating and differentiating neurons by crossing conditional β1 integrin floxed mice into the NEX-Cre transgenic line. Similar to our prior findings with conditional paxillin deficiency, we found that both homozygous and heterozygous deletion of β1 integrin causes transient mispositioning of cortical neurons in the developing cortex when analyzed pre- and perinatally. Paxillin and β1 integrin colocalize in the migrating neurons and deletion of paxillin in the migrating neuron causes an overall reduction of the β1 integrin immunofluorescence signal and reduction in the number of activated β1 integrin puncta in the migrating neurons. These findings suggest that these molecules may form a functional complex in migrating neurons. Similarly, there was an overall reduced number of paxillin+ puncta in the β1 integrin deficient neurons, despite the normal distribution of FAK and Cx26, a connexin required for cortical migration. The double knockout of paxillin and β1 integrin produces a cortical malpositioning phenotype similar to the paxillin or β1 integrin single knockouts, as would be expected if paxillin and β1 integrin function on a common pathway. Importantly, an isolation-induced pup vocalization test showed that β1 integrin mutants produced a significantly smaller number of calls compared to their littermate controls when analyzed at postnatal day 4 (P4) and revealed a several days trend in reduced vocalization development compared to controls. The current study establishes a role for β1 integrin in cortical development and suggests that β1 integrin deficiency leads to migration and neurodevelopmental delays.

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Section: Discussionmentioning

confidence: 99%

Delayed cortical development in mice with a neural specific deletion of β1 integrin

Rashid

Olson

2023

Front. Neurosci.

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Interferon-γ enhances neocortical synaptic inhibition by promoting membrane association and phosphorylation of GABAA receptors in a protein kinase C-dependent manner

Janach

Böhm

Döhne

et al. 2022

Brain, Behavior, and Immunity

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Protein translation rate determines neocortical neuron fate

Borisova,

Newman,

Couce Iglesias

et al. 2024

Nat Commun

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The mammalian neocortex comprises an enormous diversity regarding cell types, morphology, and connectivity. In this work, we discover a post-transcriptional mechanism of gene expression regulation, protein translation, as a determinant of cortical neuron identity. We find specific upregulation of protein synthesis in the progenitors of later-born neurons and show that translation rates and concomitantly protein half-lives are inherent features of cortical neuron subtypes. In a small molecule screening, we identify Ire1α as a regulator of Satb2 expression and neuronal polarity. In the developing brain, Ire1α regulates global translation rates, coordinates ribosome traffic, and the expression of eIF4A1. Furthermore, we demonstrate that the Satb2 mRNA translation requires eIF4A1 helicase activity towards its 5’-untranslated region. Altogether, we show that cortical neuron diversity is generated by mechanisms operating beyond gene transcription, with Ire1α-safeguarded proteostasis serving as an essential regulator of brain development.

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Adhesion dynamics in the neocortex determine the start of migration and the post-migratory orientation of neurons

Cited by 4 publications

References 64 publications

Delayed cortical development in mice with a neural specific deletion of β1 integrin

Delayed cortical development in mice with a neural specific deletion of β1 integrin

Interferon-γ enhances neocortical synaptic inhibition by promoting membrane association and phosphorylation of GABAA receptors in a protein kinase C-dependent manner

Protein translation rate determines neocortical neuron fate

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