# Enhanced NGR/p75/KAL9 Signaling and Impaired Dendritic Morphogenesis across Development

> **NIH NIH K08** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2021 · $189,540

## Abstract

Schizophrenia (SZ) is a severe, persistent psychiatric disorder whose molecular underpinnings remain largely
unknown. A highly replicated pathological feature identified in postmortem tissue studies is decreased dendritic
length and complexity in Layer 3 pyramidal cells (L3 PCs), found across multiple cortical regions. Dendritic length
and branching determine a PCs receptive field, help to segment computational compartments, and contribute
substantially to how the received signals are integrated and transmitted to the cell body. Thus, there is a
compelling need to investigate the molecular pathogenesis of dendritic length and branching alterations in SZ,
as these reductions may directly contribute to disease pathology. Dendritic morphogenesis is restricted by
signaling via a complex of Nogo receptor (NGR), p75, and the KAL9 isoform of Kalirin (KAL). KAL9 activates
RhoA downstream of this pathway. Increased levels of Nogo mRNA as well as elevated levels of KAL9 protein
have been described in SZ, suggesting enhanced activity of this pathway may contribute to dendritic impairments
in SZ. We have found that a missense mutation near the RhoA domain in KAL9 (KALRN-PT) can model gain of
function in this pathway: 1) Enhancing RhoA activity downstream of KAL9, 2) Downregulating expression of
genes for microtubule transport proteins and 3) Recapitulating the reductions in dendritic length and complexity
observed in SZ. I propose studies to test the hypothesis that enhanced activity in the NGR/p75/KAL9 pathway
downregulates the expression of microtubule transport proteins and subsequently impairs dendritic
morphogenesis in PCs across development. I have generated a genetic mouse model containing the KALRN-
PT missense mutation at the endogenous locus as a novel tool to study enhanced NGR/p75/KAL9 pathway
activity. First, I will test the influence of KALRN-PT on dendritic morphogenesis in vivo in L3 PCs across the
developmental epoch that coincides with SZ risk in humans. Second, I will use RNA-sequencing on laser capture
microdissection samples of L3 PCs from KALRN-PT mice to identify altered transcripts downstream of
NGR/p75/KAL9 signaling. Finally, I will test the ability of NGR/p75/KAL9 pathway inhibition to rescue structural
impairments in PCs in organotypic slice culture, and subsequently characterize the molecular profile of these
rescued neurons to identify specific therapeutic targets responsible for rescue. Integrated with this research
project is training to: 1) Develop expertise in mechanisms of impaired dendritic morphogenesis relevant to SZ.
2) Expand knowledge of how pyramidal cell development is influenced by circuits and age. 3) Develop expertise
in using animal models of the developmental progression of disease pathology. 4) Expand my skills in advanced
analytics and bioinformatics. This unique training will provide me with the necessary background to establish an
independent, NIH-funded laboratory making innovative contributions to the mol...

## Key facts

- **NIH application ID:** 10115532
- **Project number:** 5K08MH118513-03
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Melanie Jean Grubisha
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $189,540
- **Award type:** 5
- **Project period:** 2019-02-01 → 2023-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10115532

## Citation

> US National Institutes of Health, RePORTER application 10115532, Enhanced NGR/p75/KAL9 Signaling and Impaired Dendritic Morphogenesis across Development (5K08MH118513-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10115532. Licensed CC0.

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