XNGNR1-dependent neurogenesis mediates early neural cell death

Abstract

Early neural cell death is programmed cell death occurring within proliferating and undifferentiated neural progenitors. Little is known about the regulation and role of early neural cell death. In Xenopus embryos, primary neurogenesis is disrupted following the inhibition of early neural cell death, indicating that it is required for normal primary neurogenesis. Here we show that early neural cell death is dependent on primary neurogenesis. Overexpression of XSoxD concomitantly reduced N-Tubulin expression and early neural cell death, as seen by reduced TUNEL staining in stage 15 embryos. Conversely, overexpression of XNgnr1 led to ectopic N-Tubulin expression and TUNEL staining. However, XNeuroD overexpression, which induces ectopic N-Tubulin expression downstream of XNgnr1, had no effect on early neural cell death. E1A12S differentially inhibits the differentiation pathway induced by XNGNR1 protein. E1A12S-mediated inhibition of XNGNR1 neurogenic activity resulted in the reduction of N-Tubulin expression and TUNEL staining. Taken together, our data establish that primary neurogenesis induced by XNGNR1 promotes early neural cell death. This indicates that XNgnr1 positively regulates early neural cell death. We propose that early neural cell death might eliminate cells with abnormally high levels of XNGNR1, which can result in pre-mature neuronal differentiation.

Regulation of neurogenin stability by ubiquitin-mediated proteolysis

“…During development, NGN expression is transient, and prolonged up-regulation by mRNA microinjection can result in apoptosis [29]. NeuroD is downstream of NGN and drives terminal differentiation of neurons [12].…”

The E3 ubiquitin ligase skp2 regulates neural differentiation independent from the cell cycle

“…At the levels injected here, the co-injection of Xic1, skp2 and XNgnr1 frequently results in apoptosis, precluding further investigation. This may be a result of the combined mild pro-apoptotic effects of both XNgnr1 and Xic1 [ 22 , 65 ] when they are co-injected. We would note, however, that Xngnr1 is the endogenous driver of formation of primary neurons in the normal stripes, these are suppressed by over-expression of skp2, and a partial rescue occurs when skp2 and Xic1 are co-injected.…”

Mcl1 protein levels and Caspase‐7 executioner protease control axial organizer cells survival

“…Other studies performed in amphibians describe a role for the apoptotic machinery in primary neurogenesis. 8,17 Currently, the intracellular signals that influence cell survival at these early developmental stages remain unknown (reviewed in References 4,6. Extensive work in the nematode Caenorhabditis elegans (C. elegans), the fruit fly Drosophila, and vertebrates, including mammals, has led to a better understanding of the mechanisms driving cell death, revealing that apoptosis is implemented through the activation of a conserved molecular pathway (reviewed in References 3,[18][19][20][21] Cell death signals ultimately drive the activation of initiator Caspase-9 and effector Caspases, such as Caspase-3 (Casp3) and Caspase-7 (Casp7), which leads to self-activation of Caspases by proteolytic cleavage and irreversibly to cell death by triggering degradation of the DNA and other vital cell components (reviewed in References 22-24. Noteworthy both initiator and effector Caspases display nonapoptotic activities that participate in the terminal differentiation of specialized cells, specifically in rodent lens epithelial cells 25 and in human keratinocytes.…”