Biology subjects

Vallee, R. B.

Publications and source records attributed to Vallee, R. B..

4 recordsLinked to original sources

bioRxiv2024

The Role of Nde1 Phosphorylation in Interkinetic Nuclear Migration and Schizophrenia

Nde1 is a cytoplasmic dynein regulatory protein with important roles in vertebrate brain development. One noteworthy function is in the nuclear oscillatory behavior in neural progenitor cells, the control and mechanism of which remain poorly understood. Nde1 contains multiple phosphorylation sites for the cell cycle-dependent protein kinase CDK1, though the function of these sites is not well understood. To test their role in brain development we expressed phosphorylation-state mutant forms of Nde1 in embryonic rat brains using in utero electroporation. We find that Nde1 T215 and T243 phosphomutants block apical interkinetic nuclear migration (INM) and, consequently, mitosis in radial glial progenitor cells. Another Nde1 phosphomutant at T246 also interfered with mitotic entry without affecting INM, suggesting a more direct role for Nde1 T246 in mitotic regulation. We also found that the Nde1 S214F mutation, which is associated with schizophrenia, inhibits CDK5 phosphorylation at an adjacent residue which causes alterations in neuronal lamination. These results together identify important new roles for Nde1 phosphorylation in neocortical development and disease and represent the first evidence for Nde1 phosphorylation roles in INM, neuronal lamination, and schizophrenia. Significance StatementThe results presented in this study show the importance of Nde1 phosphoregulation during successive stages of neocortical development. Nde1 dysregulation may, in turn, have important consequences in human psychiatric disorders, such as schizophrenia, as well. We observed clear and potent effects of specific Nde1 phosphomutants in the control of INM and neural development. Our results provide strong support for new insight into the little-understood mechanism for triggering RGP mitotic entry. In the course of these studies, we obtained clear evidence for a novel post-mitotic role for Nde1 phosphorylation in schizophrenia.

developmental biology↗

bioRxiv2023

The Nucleoporin Nup153 Is the Anchor for Kif1a during Basal Nuclear migration in Brain Progenitor Cells

Radial glial progenitors (RGPs) are highly elongated epithelial cells that give rise to most stem cells, neurons, and glia, in the vertebrate cerebral cortex. During development the RGP nuclei exhibit a striking pattern of cell cycle-dependent oscillatory movements known as interkinetic nuclear migration (INM), which we previously found to be mediated during G1 by the kinesin Kif1a, and during G2 by cytoplasmic dynein, recruited to the nuclear envelope by the nucleoporins RanBP2 and Nup133. We now identify Nup153 as a nucleoporin anchor for Kif1a, responsible for G1-specific basal nuclear migration, providing a complete model for the mechanisms underlying this basic, but mysterious behavior, with broad implications for understanding brain development.

neuroscience↗

bioRxiv2018

Glycogen Synthase Kinase 3 induces multilineage maturation of human pluripotent stem cell-derived lung progenitors in 3D culture.

Although strategies for directed differentiation of human pluripotent stem cells (hPSCs) into lung and airway have been established, terminal maturation of the cells remains a vexing problem. We show here that in Collagen I 3D cultures in the absence of glycogen synthase kinase 3 (GSK3) inhibition, hPSC-derived lung progenitors (LPs) undergo multilineage maturation into proximal cells arranged in pseudostratified epithelia, type I alveolar epithelial cells and morphologically mature type II cells. Enhanced cell cycling, one of the signaling outputs of GSK3 inhibition, plays a role in the maturation-inhibiting effect of GSK3 inhibition. Using this model, we show NOTCH signaling induced a distal at the expense of a proximal and ciliated cell fate, while WNT signaling promoted a proximal, club cell fate, thus implicating both signaling pathways in proximodistal specification in human lung development. These findings establish an approach to achieve multilineage maturation of lung and airway cells from hPSCs, demonstrate a pivotal role of GSK3 in the maturation of lung progenitors, and provide novel insight into proximodistal specification during human lung development.

developmental biology↗

bioRxiv2017

Replication of early and recent Zika virus isolates throughout mouse brain development

Fetal infection with Zika virus (ZIKV) can lead to congenital Zika virus syndrome (cZVS), which includes cortical malformations and microcephaly. The aspects of cortical development that are affected during virus infection are unknown. Using organotypic brain slice cultures generated from embryonic mice of various ages, sites of ZIKV replication including the neocortical proliferative zone and radial columns, as well as the developing midbrain, were identified. The infected radial units are surrounded by uninfected cells undergoing apoptosis, suggesting that programmed cell death may limit viral dissemination in the brain and may constrain virus associated injury. Therefore, a critical aspect of ZIKV induced neuropathology may be defined by death of uninfected cells. All ZIKV isolates assayed replicated efficiently in early and mid-gestation cultures, and two isolates examined replicated in late-gestation tissue. Alteration of neocortical cytoarchitecture, such as disruption of the highly-elongated basal processes of the radial glial progenitor cells, and impairment of postmitotic neuronal migration were also observed. These data suggest that all lineages of ZIKV tested are neurotropic, and that ZIKV infection interferes with multiple aspects of neurodevelopment that contribute to the complexity of cZVS.\n\nSignificanceZika virus infection has been associated with multiple pathologies of the central nervous system (CNS) including microcephaly, Guillain-Barre syndrome, lissencephaly, the loss of white and grey matter volume and acute myelitis. Using organotypic brain slice cultures, we determined that ZIKV replicates across different embryonic developmental stages, and viral infection can disrupt proper brain development leading to congenital CNS complications. These data illustrate that all lineages of ZIKV tested are neurotropic, and that infection may disrupt neuronal migration during brain development. The results expand our understanding of neuropathologies associated with congenital Zika virus syndrome.

microbiology↗