Saffarian, A. | bioRxiv Science

bioRxiv2021

The Amyloid Precursor Protein regulates human cortical neurogenesis

The approximately 16 billion neurons of the human neocortex are derived from a relatively limited number of developmental neural stem cells (NSCs). During embryogenesis, human cortical NSCs initially generate neurons at a particularly slow rate while preserving their progenitor state for a relatively long time. How this balance between the progenitor state and neurogenic state is regulated, and whether it contributes to species-specific brain patterning, is poorly understood. Here we show that the characteristic potential of human NSCs to remain in a progenitor state as they generate neurons for a prolonged amount of time requires the Amyloid Precursor Protein (APP). In contrast, APP is dispensable in mouse NSCs, which undergo neurogenesis at a much faster rate. Mechanistically, loss of APP cell-autonomously accelerates neurogenesis through activation of the AP1 transcription factor and repression of WNT signaling. We propose that the fine balance between self-renewal and differentiation is homeostatically regulated by APP, which may contribute to human-specific temporal patterns of neurogenesis.

developmental biology↗

bioRxiv2020

IlvY is an important regulator of Shigella infection in vitro and in vivo

Shigellosis results from oral ingestion of the Gram-negative bacteria Shigella, and symptoms include severe diarrhea and dysentery. In the absence of vaccines, small molecule antibacterial drugs have provided treatment options for shigellosis. However, Shigella drug resistance is rapidly emerging, and Shigella strains with resistance to both third-generation cephalosporins and azithromycin have been identified in Asia. A re-conceptualization is needed regarding the development of therapeutics that target bacterial pathogens in order to reduce resistance development and alteration of gut microbiota, which is depleted upon treatment with wide spectrum antibiotics, thereby increasing susceptibility to subsequent enteric infections. A more organism-specific approach is to develop agents targeting virulence factors such as toxins, adhesins, invasins, quorum sensing, and protein secretion systems. For Shigella, there is interest in targeting transcription factors essential for Shigella infection in vivo rather than specific effectors. Here we describe the importance of the Shigella transcription factor IlvY in Shigella virulence in vitro and in vivo. This work included the development of a novel, oral mouse model of Shigella infection with wild-type adult mice. Unlike previous models, mice do not require antibiotic pretreatment or diet modifications. This mouse model was used to demonstrate the importance of IlvY for Shigella in vivo survival and that deletion of ilvY impacts host responses to infection. These results illustrate that IlvY is a potential therapeutic target for the treatment of shigellosis. In addition, the novel mouse model provides an exciting new opportunity to investigate therapeutic efficacy against Shigella infection and host responses to infection.

microbiology↗