How are necrotic neurons recognized by their phagocytes

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In an animal’s life, a large number of cells undergo apoptosis – cell suicide, to support development and maintain body homeostasis. In addition, during stroke, cancer, and other traumatic situations, a large number of cells undergo necrosis after injury. These cells are rapidly internalized by other cells via phagocytosis (engulfment) and degraded inside engulfing cells. The swift removal of dying cells prevents tissue injury, inflammatory responses, and auto-immune responses, clears the wounded area, and promotes tissue repair. Necrosis is also closely associated with neuron degeneration. The phagocytosis of necrotic neurons and axon debris facilitates the repair and recovery of neuron functions. Phagocytic activity by the microglia also contribute to the loss of synapses in Alzheimer’s disease. My long-term goal is to understand how dying cells are specifically recognized, internalized, and degraded by engulfing cells, using the nematode Caenorhabditis elegans as a model organism. As many physiological mechanisms are highly conserved throughout evolution, what we learn from C. elegans can be translated to humans. This proposal investigates the mechanisms that promote the exposure of phosphatidylserine (PS), an “eat me” signal, on the surfaces of necrotic and apoptotic cells to attract engulfing cells. In C. elegans, the necrosis of six mechanosensory neurons (also called touch neurons) is induced by mutations in a particular group of plasma membrane ion channel proteins, including the dominant mutations in MEC-4, a subunit of the mechanosensory Na+ channel. We found that two proteins, the ABC transporter CED-7, and ANOH-1, the worm homolog of the mammalian phospholipid scramblase TMEM16F, act in parallel to promote PS exposure on the surfaces of necrotic cells. Recently, we have identified that the exposure of PS on necrotic cells is mediated by cytoplasmic Ca2+. Furthermore, we discovered two alternative mechanisms that increase Ca2+ level in the cytoplasm, one dependent on the release of Ca2+ from the endoplasmic reticulum (ER), the other independent of the ER. In addition, we have identified multiple genes that act to regulate PS exposure. To further investigate the molecular mechanism(s) of PS exposure, I propose to determine the novel functions of a transthyretin-like protein and a proposed PS flippase in promoting the exposure of PS on the surfaces of necrotic cells in response to the Ca2+ signaling (Aims 1 and 2), and to identify new PS-exposure genes from mutants defective in the exposure of PS on dying cells that we isolated in a forward genetic screen (Aim 3). Together, the outcomes will allow us to establish pathways that promote PS exposure in response to upstream signals. They will also reveal novel molecular mechanisms regulating each step of the process, some of which are anticipated to be unique to necrotic or apoptotic cells.