Jagged1 is Essential for Radial Glial Maintenance in the Cortical Proliferative Zone

Blackwood, Christopher A.

doi:10.1016/j.neuroscience.2019.05.062

Cited by 11 publications

(15 citation statements)

References 44 publications

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“…Moreover, the number of NS showed a substantial difference between the mutants (Figure 4R). These findings suggest that Jag1 is required for the maintenance of stem-like cells in vitro, confirming previous findings that Jag1 is required for the maintenance of stem cells in vivo (Nyfeler et al, 2005;Blackwood, 2019).…”

Section: Dlx2supporting

confidence: 91%

“…The number of NS formed is an indicator of the number of actively dividing neural stem/progenitor cells. In our previous study, deletion of Jag1 in homozygous mutants showed fewer numbers of NS (Blackwood, 2019); however, whether this phenotype is recapitulated in heterozygous mutants was not performed. We therefore, re-examined the loss of Jag1 on the formation of primary NS.…”

Section: Dlx2mentioning

confidence: 85%

“…Neurospheres (NS) were generated from the dorsal LGE (dLGE) region of individual E17.5 embryos using a similar method previously described in Blackwood (2019), but independent cultures were used to re-examine the in vitro phenotype. The two hemispheres were separated and the area around the lateral ventricles was carefully isolated.…”

Section: Neurosphere Assaymentioning

confidence: 99%

“…The loss of Jag1 causes premature neuronal differentiation in NS derived from the dLGE (Blackwood, 2019). Next, we asked whether there were any imbalances in differentiation of TH or GluR1 interneurons and proliferation in the OB.…”

Section: Haploinsufficient Jag1 Displays Defects In the Generation Ofmentioning

confidence: 99%

“…The postnatal SVZ in mice is essential for the production of mature interneurons within the olfactory bulb (OB) (Doetsch et al, 1999;Lim and Alvarez-Buylla, 2016). Jag1 has been shown to be essential for maintaining proliferation in the cortical SVZ (Blackwood, 2019) and postnatal SVZ (Nyfeler et al, 2005). Whether Jag1 level is critical in the development of embryonically derived interneurons within the OB remains elusive.…”

Section: Introductionmentioning

confidence: 99%

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Notch Dosage: Jagged1 Haploinsufficiency Is Associated With Reduced Neuronal Division and Disruption of Periglomerular Interneurons in Mice

Blackwood

Bailetti

Nandi

et al. 2020

Front. Cell Dev. Biol.

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Neural stem cells in the lateral ganglionic eminence (LGE) generate progenitors that migrate through the rostral migratory stream (RMS) to repopulate olfactory bulb (OB) interneurons, but the regulation of this process is poorly defined. The evolutionarily conserved Notch pathway is essential for neural development and maintenance of neural stem cells. Jagged1, a Notch ligand, is required for stem cell maintenance. In humans, heterozygous mutations in JAGGED1 cause Alagille syndrome, a genetic disorder characterized by complications such as cognitive impairment and reduced number of bile ducts in the liver, suggesting the presence of a JAGGED1 haploinsufficient phenotype. Here, we examine the role of Jagged1 using a conditional loss-of-function allele in the nervous system. We show that heterozygous Jagged1 mice possess a haploinsufficient phenotype that is associated with a reduction in size of the LGE, a reduced proliferative state, and fewer progenitor cells in the LGE and RMS. Moreover, loss of Jagged1 leads to deficits in periglomerular interneurons in the OB. Our results support a dose-dependent role for Jagged1 in maintaining progenitor division within the LGE and RMS.

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Section: Dlx2supporting

confidence: 91%

Section: Dlx2mentioning

confidence: 85%

Section: Neurosphere Assaymentioning

confidence: 99%

Section: Haploinsufficient Jag1 Displays Defects In the Generation Ofmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Notch Dosage: Jagged1 Haploinsufficiency Is Associated With Reduced Neuronal Division and Disruption of Periglomerular Interneurons in Mice

Blackwood

Bailetti

Nandi

et al. 2020

Front. Cell Dev. Biol.

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Loss of PP2A Disrupts the Retention of Radial Glial Progenitors in the Telencephalic Niche to Impair the Generation for Late-Born Neurons During Cortical Development†

et al. 2020

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Telencephalic radial glial progenitors (RGPs) are retained in the ventricular zone (VZ), the niche for neural stem cells during cortical development. However, the underlying mechanism is not well understood. To study whether protein phosphatase 2A (PP2A) may regulate the above process, we generate Ppp2cα conditional knockout (cKO) mice, in which PP2A catalytic subunit α (PP2Acα) is inactivated in neural progenitor cells in the dorsal telencephalon. We show that RGPs are ectopically distributed in cortical areas outside of the VZ in Ppp2cα cKO embryos. Whereas deletion of PP2Acα does not affect the proliferation of RGPs, it significantly impairs the generation of late-born neurons. We find complete loss of apical adherens junctions (AJs) in the ventricular membrane in Ppp2cα cKO cortices. We observe abundant colocalization for N-cadherin and PP2Acα in control AJs. Moreover, in vitro analysis reveals direct interactions of N-cadherin to PP2Acα and to β-catenin. Overall, this study not only uncovers a novel function of PP2Acα in retaining RGPs into the VZ but also demonstrates the impact of PP2A-dependent retention of RGPs on the generation for late-born neurons.

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A simple method for gene expression in endo- and ectodermal cells in mouse embryos before neural tube closure

Kuwayama

Kishi

Maeda

et al. 2020

Preprint

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22During the early stage of mammalian neural development, neuroepithelial cells (NECs) 23 proliferate and increase their pool size before switching their fate to become neurogenic 24 radial glial progenitors (RGPs). The timing of this expansion-to-neurogenic phase 25 transition is strictly regulated so as to determine the proper number of progenitors and 26 differentiated cell types that constitute the brain. The molecular mechanism underlying 27 this switch has remained poorly understood, however, in part because of the difficulty 28 associated with manipulation of gene expression in NECs before their transition to 29 RGPs, which occurs before neural tube closure. We have now developed a simple and 30 efficient method to manipulate gene expression in mouse neocortical NECs in the 31 expansion phase by in utero injection of viral vectors at embryonic day 7.0 to 8.0. With 32 the use of this method, we found that knockdown of the chromatin-associated protein 33Hmga2 in NECs inhibited the onset of the neurogenic phase in the neocortex. This 34 effect of Hmga2 knockdown was accompanied by inhibition of the expression of a set 35 of genes targeted by Polycomb group proteins, which repress neurogenic genes in 36 cortical progenitors. Our study thus establishes a novel method for manipulation of gene 37 expression in the early stage of mouse brain development as well as uncovers a key 38 molecular player in the generation of neurogenic progenitors in the developing mouse 39 neocortex. 40 41 E8.0. This method is based on in utero injection of viral vectors into amniotic fluid and 130 is associated with a high survival rate without inducing gross developmental 131 abnormalities. Moreover, as a proof of concept, we have identified a key regulator of 132 the E-to-N transition with the use of this new method. We found that Hmga2 expression 133 in neocortical NPCs peaks at around the E-to-N transition (at E10), and that knockdown 134 of Hmga2 from E8.0 delayed the onset of neurogenesis and shifted the transcriptional 135 profile of NPCs at this transition closer to that in the expansion phase. Importantly, 136 knockdown of Hmga2 from E8.0 attenuated the expression of a subset of PcG target 137 genes in NPCs at E11.0. Our results suggest that an increase in Hmga2 expression 138 triggers the onset of the neurogenic phase in part through activation of neurogenesis-139

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Jagged1 is Essential for Radial Glial Maintenance in the Cortical Proliferative Zone

Cited by 11 publications

References 44 publications

Notch Dosage: Jagged1 Haploinsufficiency Is Associated With Reduced Neuronal Division and Disruption of Periglomerular Interneurons in Mice

Notch Dosage: Jagged1 Haploinsufficiency Is Associated With Reduced Neuronal Division and Disruption of Periglomerular Interneurons in Mice

Loss of PP2A Disrupts the Retention of Radial Glial Progenitors in the Telencephalic Niche to Impair the Generation for Late-Born Neurons During Cortical Development†

A simple method for gene expression in endo- and ectodermal cells in mouse embryos before neural tube closure

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