Ribosome biogenesis dysfunction leads to p53-mediated apoptosis and goblet cell differentiation of mouse intestinal stem/progenitor cells.

Ribosome biogenesis is an essential cellular process. Its impairment is associated with developmental defects and increased risk of cancer. The in vivo cellular responses to defective ribosome biogenesis and the underlying molecular mechanisms are still incompletely understood. In particular, the consequences of impaired ribosome biogenesis within the intestinal epithelium in mammals have not been investigated so far. Here we adopted a genetic approach to investigate the role of Notchless (NLE), an essential actor of ribosome biogenesis, in the adult mouse intestinal lineage. Nle deficiency led to defects in the synthesis of large ribosomal subunit in crypts cells and resulted in the rapid elimination of intestinal stem cells and progenitors through distinct types of cellular responses, including apoptosis, cell cycle arrest and biased differentiation toward the goblet cell lineage. Similar observations were made using the rRNA transcription inhibitor CX-5461 on intestinal organoids culture. Importantly, we found that p53 activation was responsible for most of the cellular responses observed, including differentiation toward the goblet cell lineage. Moreover, we identify the goblet cell-specific marker Muc2 as a direct transcriptional target of p53. Nle-deficient ISCs and progenitors disappearance persisted in the absence of p53, underlying the existence of p53-independent cellular responses following defective ribosome biogenesis. Our data indicate that NLE is a crucial factor for intestinal homeostasis and provide new insights into how perturbations of ribosome biogenesis impact on cell fate decisions within the intestinal epithelium.

Facilitation of human first dorsal interosseous muscle responses to transcranial magnetic stimulation during voluntary contraction of the contralateral homonymous muscle.

The size of compound motor evoked potentials (cMEPs) to transcranial magnetic stimulation of the motor cortex was measured in the relaxed first dorsal interosseous muscle of the nondominant hand (ndFDI) during different levels of voluntary contraction in the homonymous muscle of the dominant hand (dFDI). cMEP responses in the ndFDI became larger when the dFDI was contracted to forces ranging 10-70% of maximum voluntary contraction. Variability in the amplitude of the cMEP responses in ndFDI decreased when dFDI was contracted. Comparison with cMEPs to spinal cord stimulation suggested a large component of the facilitation was occurring at a cortical level. The amplitude of cMEP responses in ndFDI also increased when the tibialis anterior muscle of the leg on the contralateral side was contracted. The observed facilitation of motoneurons during contraction of contralateral muscles might involve a transcallosal pathway modulating the excitability of one cortex when the other is activated.