# Elucidating the origins of cortical tuber cells using human brain organoid models of TSC

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA BERKELEY · 2021 · $388,200

## Abstract

PROJECT SUMMARY
 Tuberous Sclerosis Complex (TSC) is a multi-system developmental disorder caused by mutations in
the TSC1 or TSC2 genes. The protein products of these genes form a complex that is an essential negative
regulator of mTORC1 signaling. In the absence of a functional TSC1/2 complex, mTORC1 signaling is
deregulated and constitutively active. While the manifestations of TSC can affect several different organ
systems, the neurological and psychiatric aspects of the disease are the most burdensome for caregivers and
least well understood. These include early-onset epilepsy, varying degrees of intellectual disability, and a high
prevalence of autism spectrum disorder and other behavioral conditions. A hallmark pathology of TSC is the
presence of cortical tubers, which are focal regions of enlarged, dysplastic neurons and glia in the cortex that
form during embryonic development. Cortical tubers can become epileptic foci and in some cases are
surgically removed in individuals with intractable seizures. The size and number of cortical tubers is variable
between patients and increased cortical tuber load is associated with worse outcomes including more severe
epilepsy and cognitive impairment.
 The goal of this project is to determine the molecular mechanism(s) by which mutations in TSC1 or
TSC2 lead to the formation of cortical tuber cells. To do this we will use our recently established human brain
organoid models of TSC in which we have engineered loss of function mutations in TSC1 or TSC2. These
human brain organoid models robustly reproduce key cellular features of cortical tubers including dysmorphic
neurons, reactive astrocytes, and giant/balloon cells. In addition, we have observed a strong bias towards the
production of glial-lineage cells at the expense of neurons in TSC brain organoids, which recapitulates
observations from patient tuber samples. Here we will define the molecular basis for altered cortical cell
development due to TSC1/2 mutations and investigate how the resulting tuber cells impact the function of the
surrounding cortical network. In Aim 1 we will explore two potential hypotheses for altered differentiation of
TSC1/2 mutant cells in brain organoids: 1) premature activation of astrogenic transcription programs that
interfere with normal neurogenesis and/or 2) impaired survival and development of newborn neurons. To test
these hypotheses we will use pharmacological, shRNA, and CRISPRi manipulations to test the contribution of
candidate pathways. In Aim 2 we will use different strategies to manipulate mTORC1 signaling and specific
downstream arms of the pathway to test whether these can prevent or rescue altered cellular development. In
Aim 3, we will perform functional analyses to determine how the presence of cortical tuber cells impacts the
activity of the surrounding cortical network. Together the results of these aims will generate new insights into
the molecular and cellular mechanisms leading to cortical tuber...

## Key facts

- **NIH application ID:** 10122032
- **Project number:** 2R01NS097823-06
- **Recipient organization:** UNIVERSITY OF CALIFORNIA BERKELEY
- **Principal Investigator:** Helen S. Bateup
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $388,200
- **Award type:** 2
- **Project period:** 2016-05-15 → 2026-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10122032

## Citation

> US National Institutes of Health, RePORTER application 10122032, Elucidating the origins of cortical tuber cells using human brain organoid models of TSC (2R01NS097823-06). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10122032. Licensed CC0.

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