RESUMEN
Pkhd1l1 is predicted to encode a very large type-I transmembrane protein, but its function has largely remained obscure. Recently, it was shown that Pkhdl1l1 is a component of the coat that decorates stereocilia of outer hair cells in the mouse ear. Consistent with this localization, conditional deletion of Pkhd1l1 specifically from hair cells, was associated with progressive hearing loss. In the zebrafish, there are two paralogous pkhd1l1 genes - pkhd1l1α and pkhd1l1ß. Using CRISPR-Cas9 mediated gene editing, we generated loss-of-function alleles for both and show that the double mutants exhibit nonsense-mediated-decay (NMD) of the RNAs. With behavioural assays, we demonstrate that zebrafish pkhd1l1 genes also regulate hearing; however, in contrast to Pkhd1l1 mutant mice, which develop progressive hearing loss, the double mutant zebrafish exhibited statistically significant hearing loss even from the larval stage. Our data highlight a conserved function of Pkhd1l1 in hearing and based on these findings from animal models, we postulate that PKHD1L1 could be a candidate gene for sensorineural hearing loss (SNHL) in humans.
RESUMEN
The influence of the naturally occurring population of microbes on various human diseases has been a topic of much recent interest. Not surprisingly, continuously growing attention is devoted to the existence of a gut brain axis, where the microbiota present in the gut can affect the nervous system through the release of metabolites, stimulation of the immune system, changing the permeability of the blood-brain barrier or activating the vagus nerves. Many of the methods that stimulate the nervous system can also lead to the development of cancer by manipulating pathways associated with the hallmarks of cancer. Moreover, neurogenesis or the creation of new nervous tissue, is associated with the development and progression of cancer in a similar manner as the blood and lymphatic systems. Finally, microbes can secrete neurotransmitters, which can stimulate cancer growth and development. In this review we discuss the latest evidence that support the importance of microbiota and peripheral nerves in cancer development and dissemination.
RESUMEN
Tumors exhibit complex organization and contain a variety of cell populations. The realization that the regenerative properties of a tumor may be largely confined to a cell subpopulation (cancer stem cell) is driving a new era of anti-cancer research. Cancer stem cells from Glioblastoma Multiforme tumors express markers that are also expressed in non-cancerous neural stem cells, including nestin and Sox2. We previously showed that the transcription factor Hes3 is a marker of neural stem cells, and that its expression is inhibited by JAK activity. Here we show that Hes3 is also expressed in cultures from glioblastoma multiforme which express neural stem cell markers, can differentiate into neurons and glia, and can recapitulate the tumor of origin when transplanted into immunocompromised mice. Similar to observations in neural stem cells, JAK inhibits Hes3 expression. Hes3 RNA interference reduces the number of cultured glioblastoma cells suggesting a novel therapeutic strategy.