# Cellular and molecular mechanisms of brain dysfunction in NF1

> **NIH NIH R01** · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · 2022 · $398,325

## Abstract

Despite the well-recognized cognitive deficits in Neurofibromatosis type 1 (NF1), the mechanisms underlying the
neuropathophysiology remain unclear. The clear lack of translation from findings in mouse models to the clinic
manifests the inherent species differences in the development, architecture and function of rodent and human
brains, and underscores the urgent need to develop and use human model systems to study aspects of human
brain disorders and to bridge the translational gap to the clinic. Our long-term goal is to develop and use human
cellular models to elucidate the molecular and cellular mechanisms underlying the cognitive deficits associated
with NF1. Recent advances in the field of epigenetic reprogramming, stem cell biology and genetic engineering
has rendered us a unique opportunity to model neurodevelopmental disorders such as NF1 in a manner that is
highly complementary to murine transgenic approaches by that maintains fidelity with complex human cellular
contexts. The objective of the current study is to harness such tools to characterize the abnormalities in
neurodevelopment and neuronal network activity caused by NF1-associated mutations and determine the
cellular and molecular mechanisms underlying Neurofibromin 1 (NF1 encoding protein) - regulated biological
processes in different cellular contexts. Based on the preliminary data produced in the applicant’s laboratory, we
hypothesize that disease associated mutations in NF1 affect proliferation and cell fate commitment of human
neural progenitor cells that control neuronal output; and impair neuronal network activity through a potentially
human-specific mechanism. The hypothesis will be tested using two complementary cellular models: 1) human
brain organoids will be used to investigate the role of Neurofibromin 1 in human neural progenitor cell types,
especially the outer radial glial cells that are largely absent in the rodent developing cortices. A multidisciplinary
approach will be used to characterize cell type-specific defects in neuroepithelial cell expansion, migration,
differentiation, and the mitotic properties of cells; 2) induced neuronal (iN) system, which was developed by the
applicant and others, will be used to dissect the cellular mechanisms underlying the irregular neuronal network
activity observed in cultures consisting of NF1 mutant neurons. The current study would be the first systematic
investigation of Neurofibromin 1 completion of the proposed project function in the neural system using a human model system. Successful will provide novel knowledge on the role of Neurofibromin 1 in different neural
cell types that are relevant to the pathophysiology of NF1. Given the high prevalence of Autism in NF1, the
proposed research also has the potential to shed light on the key molecular and cellular mechanisms underlying
idiopathic Autism.

## Key facts

- **NIH application ID:** 10347337
- **Project number:** 5R01NS116057-03
- **Recipient organization:** ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
- **Principal Investigator:** Nan Yang
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $398,325
- **Award type:** 5
- **Project period:** 2020-04-15 → 2025-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10347337

## Citation

> US National Institutes of Health, RePORTER application 10347337, Cellular and molecular mechanisms of brain dysfunction in NF1 (5R01NS116057-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10347337. Licensed CC0.

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