# MET receptor tyrosine kinase and the development of forebrain circuits

> **NIH NIH R01** · UNIVERSITY OF ARIZONA · 2020 · $383,750

## Abstract

Human genetic studies have established MET as a prominent risk gene for autism spectrum disorder, a highly
heritable psychiatric disorder with disrupted ontogeny of neural connectivity. MET protein is a receptor tyrosine
kinase that is tightly regulated during early brain development, peaks at a period of rapid neurite growth and
synaptogenesis, and is precipitously down-regulated prior to neuronal maturation. The goal of this project is to
elucidate the nature of the time-delimited signaling by investigating how it regulates key brain development
events, including synaptogenesis, maturation, circuit connectivity and refinement. Preliminary results from the
PI's laboratory reveal that disruption of MET signaling in mice results in altered cortical interlaminar excitatory
connectivity, aberrant neuronal morphology and maturation of glutamatergic synapses, as well as impaired
circuit connectivity indicative of defective synapse pruning and circuit refinement. Using a controllable
transgenic mouse model created in the lab of the PI, this research team recently found that MET activation
engages the Rho family small GTPases, Cdc42 and Rac1, and leads to inhibition of the actin depolymerizing
factor cofilin, processes that are critical for dendritic spine morphogenesis and excitatory synapse development.
This has led to the central hypothesis that MET signaling promotes early dendritic spine morphogenesis, while
its down-regulation is required for dendritic spine and glutamatergic synapse maturation later in brain
development. In this application, the research group brings together an interdisciplinary team and takes an
integrated approach combining neuroanatomy, molecular genetics, in vivo two photon imaging, and patch clamp
electrophysiology combined with laser scanning photostimulation for circuit mapping to test the following
hypotheses: 1) developmental down-regulation of MET expression is required for normal glutamatergic synapse
maturation ; 2) persistent MET signaling impairs developmental synapse pruning and refinement cortical circuit
connectivity; and 3) disrupted MET signaling and the resulting change in forebrain developmental trajectory alter
mouse behavior. Impact: It is anticipated that successful completion of these proposed studies will define an
in-depth, mechanistic, and multifaceted role of MET in neural development and establishment of functional
connectivity in the developing forebrain. These mechanisms collectively may be unique to MET, and may
illuminate novel interventions in autism by targeting the temporal profiles of glutamatergic synapse development
in specific brain circuits.

## Key facts

- **NIH application ID:** 9913595
- **Project number:** 5R01MH111619-04
- **Recipient organization:** UNIVERSITY OF ARIZONA
- **Principal Investigator:** Shenfeng Qiu
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $383,750
- **Award type:** 5
- **Project period:** 2017-07-01 → 2022-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9913595

## Citation

> US National Institutes of Health, RePORTER application 9913595, MET receptor tyrosine kinase and the development of forebrain circuits (5R01MH111619-04). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/9913595. Licensed CC0.

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