# A p75/Ret Receptor Complex as an Integrator of Survival and Death

> **NIH NIH R01** · INDIANA UNIVERSITY INDIANAPOLIS · 2022 · $448,387

## Abstract

Throughout the developing nervous system excess neurons are generated which are nonessential, or
inappropriately connected, and are eliminated by programmed cell death (PCD). In the PNS, the extent
of apoptosis is governed by both a limited supply of survival-promoting neurotrophic factors provided by
targets of innervation, and by apoptosis-inducing competition factors secreted by “winning neurons” that
have successfully competed for these neurotrophic factors. The glial cell line-derived neurotrophic
factor (GDNF) family ligands (GFLs) are a family of potent growth factors that support the survival of
autonomic, somatosensory and spinal motor neurons. The GFLs promote survival and growth through
a common signal-transducing receptor tyrosine kinase, Ret. During this grant period we discovered that
Ret interacts with p75, a member of the TNF family of death receptors, and p75 enhances GDNF-mediated Ret activation and survival. When p75 is deleted specifically in sensory neurons,
approximately 20% are lost between P14 and adulthood, and these losses selectively occur in Ret+ nonpeptidergic nociceptors. These results indicate that p75 is required for the development of the
nonpeptidergic nociceptor lineage by fine-tuning Ret-mediated trophic support. We also found that
during PCD in sympathetic neurons of the superior cervical ganglion (SCG) Ret is restricted to a subset
of degenerating neurons that rapidly undergo apoptosis. Pro-apoptotic conditions induce the
association of Ret with p75, thereby enhancing the regulated intramembrane proteolysis (RIP) cleavage
of p75 and activation of downstream apoptotic effectors. Deletion of p75 in Ret+ neurons, and deletion
of Ret, specifically during PCD, inhibits apoptosis both in vitro and in vivo. These results indicate that
Ret acts non-canonically to augment p75-mediated apoptosis. The molecular mechanisms that underlie
the ability of p75 to enhance Ret signaling, and for Ret to enhance p75 mediated death, are not well
understood, and are the subject of Aim 1. We also discovered recently that semaphorin 3A (Sema3A),
a secreted repulsive axon guidance molecule, induces apoptosis of primary SCG neurons, and that
deletion of its receptor components, Neuropilin-1 (Npn-1) and PlexinA3 (PA3), significantly reduce PCD
in the SCG. Sema3A induces apoptosis via the extrinsic pathway, requiring caspase-8, as opposed to
the intrinsic pathway triggered by NGF withdrawal in sympathetic neurons that requires caspase-9. The
combination of apoptosis induced by neurotrophic factor deprivation and death receptor activation in
the developing SCG raises the question of the extent to which caspase-8 and caspase-9 contribute to
apoptosis during PCD, and which death receptors are driving this process. These questions will be the
subject of Aim 2. Collectively the experiments proposed here will define the molecular mechanisms and
magnitude of the role played by death receptor pathways, such as Npn-1/PA3 and p75, in PCD.

## Key facts

- **NIH application ID:** 10399409
- **Project number:** 5R01NS089585-09
- **Recipient organization:** INDIANA UNIVERSITY INDIANAPOLIS
- **Principal Investigator:** Brian Anthony Pierchala
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $448,387
- **Award type:** 5
- **Project period:** 2015-05-15 → 2025-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10399409

## Citation

> US National Institutes of Health, RePORTER application 10399409, A p75/Ret Receptor Complex as an Integrator of Survival and Death (5R01NS089585-09). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10399409. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*