A Dynamic Unfolded Protein Response Contributes to the Control of Cortical Neurogenesis

Abstract

The cerebral cortex contains layers of neurons sequentially generated by distinct lineage-related progenitors. At the onset of corticogenesis, the first-born progenitors are apical progenitors (APs), whose asymmetric division gives birth directly to neurons. Later, they switch to indirect neurogenesis by generating intermediate progenitors (IPs), which give rise to projection neurons of all cortical layers. While a direct lineage relationship between APs and IPs has been established, the molecular mechanism that controls their transition remains elusive. Here we show that interfering with codon translation speed triggers ER stress and the unfolded protein response (UPR), further impairing the generation of IPs and leading to microcephaly. Moreover, we demonstrate that a progressive downregulation of UPR in cortical progenitors acts as a physiological signal to amplify IPs and promotes indirect neurogenesis. Thus, our findings reveal a contribution of UPR to cell fate acquisition during mammalian brain development.

BGP-15 prevents the death of neurons in a mouse model of familial dysautonomia

“…Furthermore, ALS is marked by mitochondrial dysfunction (61). Recent work has revealed that in the absence of Elp3 in mice, cortical neurogenesis is impaired because of the activation of the unfolded protein response, which is triggered by stress in the endoplasmic reticulum (9). That study and ours help elucidate the function of the Elongator complex in neurons and reveal that its absence triggers intracellular stress.…”

“…The C terminus of IKAP/ELP1 has been shown to bind c-Jun N-terminal kinase (JNK) and to regulate JNK cytosolic stress signaling (12). Loss of Elp3 in mouse cortical neurons triggers endoplasmic reticulum stress (9), and Elp3 deletion in yeast causes disruptions in mitochondrial function (10). ELP3 has been demonstrated to localize in mitochondria in HeLa cells, mouse brain, and Toxoplasma (13,14).…”

“…The protein encoded by the IKBKAP/ELP1 gene, IKAP/ELP1, is a scaffolding protein for the six-subunit Elongator complex (ELP1-ELP6), which modifies tRNAs during translation (7). Why reduction in the IKAP/ ELP1 protein results in neuronal death is unknown, and we have sought to elucidate the cellular and molecular mechanisms that cause progressive neurodegeneration in FD to help identify treatments that improve neuronal function and viability.Accumulating evidence indicates that cells from FD patients and from mouse models with deletions in the Elongator subunits Ikbkap/Elp1 or Elp3 experience intracellular stress (4,5,(8)(9)(10) resulting from the direct and/or indirect consequences of impaired translation (7, 11). The C terminus of IKAP/ELP1 has been shown to bind c-Jun N-terminal kinase (JNK) and to regulate JNK cytosolic stress signaling (12).…”

“…Accumulating evidence indicates that cells from FD patients and from mouse models with deletions in the Elongator subunits Ikbkap/Elp1 or Elp3 experience intracellular stress (4,5,(8)(9)(10) resulting from the direct and/or indirect consequences of impaired translation (7, 11). The C terminus of IKAP/ELP1 has been shown to bind c-Jun N-terminal kinase (JNK) and to regulate JNK cytosolic stress signaling (12).…”

Transcriptional regulation of intermediate progenitor cell generation during hippocampal development

“…2G; P=0.0001). The impaired IPC development observed in Nfix −/− mice could potentially occur as a result of increased direct neurogenesis from radial glia, similar to that observed in Elp3 conditional knockout mice (Laguesse et al, 2015). To determine whether this was the case we performed a 48 h BrdU chase experiment (labeling with BrdU from E13.5).…”