Frazzled/Dcc acts independently of Netrin to promote germline survival during Drosophila oogenesis

Abstract

The Netrin receptor Frazzled/Dcc (Fra in Drosophila) functions in diverse tissue contexts to regulate cell migration, axon guidance and cell survival. Fra signals in response to Netrin to regulate the cytoskeleton and also acts independently of Netrin to directly regulate transcription during axon guidance in Drosophila. In other contexts, Dcc acts as a tumor suppressor by directly promoting apoptosis. In this study, we report that Fra is required in the Drosophila female germline for the progression of egg chambers through mid-oogenesis. Loss of Fra in the germline, but not the somatic cells of the ovary, results in the degeneration of egg chambers. Although a failure in nutrient sensing and disruptions in egg chamber polarity can result in degeneration at mid-oogenesis, these factors do not appear to be affected in fra germline mutants. However, similar to the degeneration that occurs in those contexts, the cell death effector Dcp-1 is activated in fra germline mutants. The function of Fra in the female germline is independent of Netrin and requires the transcriptional activation domain of Fra. In contrast to the role of Dcc in promoting cell death, our observations reveal a role for Fra in regulating germline survival by inhibiting apoptosis.

Diverse roles for axon guidance pathways in adult tissue architecture and function

“…93 Furthermore, in the Drosophila nervous system and ovarian germline, Frazzled has Netrin-independent transcriptional activity. 94,210,211…”

“…For example, in the Drosophila ovary, germlines lacking the insect Dcc homolog, Frazzled, fail to complete oogenesis, and egg chambers undergo apoptosis. 94 In contrast, netrin is dispensable for cell survival, and global netrin-AB mutants have apparently wild-type egg chambers. 94,95 While this pattern of cell death does not fit the dependence receptor model, it raises the possibility that Frazzled may interact with cell death machinery by an alternate mechanism.…”

“…94 In contrast, netrin is dispensable for cell survival, and global netrin-AB mutants have apparently wild-type egg chambers. 94,95 While this pattern of cell death does not fit the dependence receptor model, it raises the possibility that Frazzled may interact with cell death machinery by an alternate mechanism. Similarly, netrin-Neogenin signaling in the mammary gland may impinge on the cell death machinery by an as-yet-unknown mechanism.…”

“…Global netrin-AB mutants lay fewer eggs than control counterparts, 95 although it is unclear whether that reflects tissue-intrinsic or neuronal roles for net-A. Interestingly, netrin-independent Frazzled signaling is required cell-autonomously by germ cells later in oogenesis, 94…”

“…Guidance receptors have been implicated in cell survival in other processes that are not consistent with the dependence receptor model. For example, in the Drosophila ovary, germlines lacking the insect Dcc homolog, Frazzled, fail to complete oogenesis, and egg chambers undergo apoptosis 94 . In contrast, netrin is dispensable for cell survival, and global netrin‐AB mutants have apparently wild‐type egg chambers 94,95 .…”