# A phospho-switch in delta-catenin: relationship to PDZ-domain proteins and neuron development

> **NIH NIH R01** · UNIVERSITY OF TX MD ANDERSON CAN CTR · 2020 · $438,192

## Abstract

PROJECT SUMMARY/ABSTRACT
Generation of neuronal connectivity is regulated during brain development, with the formation of synapses
being dependent on the morphology of dendrites, branch-like structures extending out from neurons.
Disruptions in dendrite formation can thus lead to atypical synaptic connectivity, associated with
neurodevelopmental disorders such as autism, schizophrenia and Cri-du-chat syndrome. Our proposal seeks
to better understand molecular processes underlying the morphology of dendrites. This will occur through
examination of two novel protein complexes we recently revealed, each involving delta-catenin. delta-Catenin
belongs the p120-subfamily of catenin proteins, whose members have are best known for their functions in
association with cadherin cell-adhesion proteins and cytoskeletal-associated partners including small-
GTPases. delta-Catenin localizes to neuronal dendrites and synapses where it functions in development and
homeostasis. Delta-catenin possesses a central armadillo-repeat domain present in most catenins, but it
additionally contains a PDZ-binding ligand at its extreme C-terminus. This PDZ-ligand binds to a number of
PDZ-domain proteins crucial for synaptic and dendritic functions. Our preliminary findings have revealed two
novel interactions between delta-catenin's PDZ-ligand and the PDZ-domain proteins Magi1 and Pdlim5. Magi1
is a member of the membrane-associated guanylate kinase (MAGUK) family that is expressed along dendrites
with enrichment within the tips at early stages, potentially relevant to a role in dendrite extension. Pdlim5 is a
PDZ-LIM protein also found in dendrites, but is believed to negatively regulate the neurite growth cone to halt
the dendrite's lengthening. Our preliminary work using rat hippocampal neurons suggests that Magi1
expression promotes the lengthening of dendrites, while Pdlim5 appears instead to enhance branching. This
presents us with the intriguing thought that two proteins with seemingly opposing roles can each bind delta-
catenin. Analysis of these interactions has revealed a critical phosphorylation site in delta-catenin's PDZ-ligand
that appears to determine which of the two interactions occurs, potentially contributing to the spatial and
temporal control of dendritic morphologies. Using primary rat hippocampal neurons as well as HEK293 cells,
the experiments proposed in this application examine the phospho-dependency (Aim 1) and the cellular and
developmental significance of the delta-catenin:Magi1 and delta-catenin:Pdlim5 complexes (Aim 2).
Experimental approaches include (among others) the selective disruption of these two delta-catenin complexes
using knock-down/ add-back strategies. Given that the dysfunction of each of the three proteins under study
are implicated in neurologic diseases, addressing their interactions and contributions to dendrite development
could provide insight to the progression of neurodevelopmental disorders.

## Key facts

- **NIH application ID:** 9924693
- **Project number:** 5R01MH115717-03
- **Recipient organization:** UNIVERSITY OF TX MD ANDERSON CAN CTR
- **Principal Investigator:** PIERRE D MCCREA
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $438,192
- **Award type:** 5
- **Project period:** 2018-09-01 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9924693

## Citation

> US National Institutes of Health, RePORTER application 9924693, A phospho-switch in delta-catenin: relationship to PDZ-domain proteins and neuron development (5R01MH115717-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9924693. Licensed CC0.

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