UCSF

Apoptosis is a highly conserved form of programmed cell death in multicellular organisms where a cell activates caspase proteases to trigger its own demise. It has critical functions under physiological conditions in removing superfluous or damaged cells from a healthy organism. However, dysregulated apoptosis plays an important role in diseases: improper or elevated apoptosis leads to diseases of cell loss, such as diabetes or neurodegeneration, while deficiencies in apoptosis can contribute to tumor cell growth and survival.

While the importance of apoptosis during late embryogenesis is well-established, its function during the earliest stages of development, namely the exit of embryonic stem cells (ESC) from the pluripotent state, is unclear. Here, I discovered that apoptosis plays a critical role in removing slow-differentiating murine ESC from the total cell population. This is initiated by p53-dependent upregulation of the Fas death receptor on straggling ESCs, which then triggers apoptosis specifically in these cells. An inability to initiate apoptosis, by transient knockdown or genetic deletion of components of this pathway, causes retention of slow-differentiating ESCs and a global delay in differentiation, both in vitro and in an in vivo teratoma model. Thus, apoptosis is crucial in promoting the efficient differentiation of ESCs.

While apoptosis is important for normal development, elevated levels due to cellular stress can cause inappropriate cell loss and degeneration, leading to disease. One such example is retinitis pigmentosa, an inherited disease where rod photoreceptors are progressively lost from the neural retina, eventually leading to blindness. There is increasing evidence that accumulation of unfolded proteins within the endoplasmic reticulum (ER) of rod photoreceptors causes ER stress and subsequent cell death. Here, I utilize a novel small molecule inhibitor to show that inhibition of IRE1α, an ER transmembrane kinase/endoribonuclease that can signal both adaptation and apoptosis in response to ER stress, preserves rod photoreceptor viability and function in two rodent models of ER stress-induced photoreceptor degeneration.

These findings reveal new insights into the role of apoptosis under both normal and stressed conditions, and may have implications for human diseases such as cancer and neurodegeneration.