# In vitro modeling of a mammalian embryonic neural tube

> **NIH NIH R01** · UNIVERSITY OF VIRGINIA · 2021 · $399,144

## Abstract

Project Summary
 Creating in vitro models of mammalian neural development amenable to experimental manipulation and drug
screening is critically important for delineating the molecular basis of, and developing clinical therapies for,
neurological disorders that affect more than one billion people worldwide. Toward this goal, three-dimensional
neural organoids have been developed and display some structural and functional features of neural tissues.
However, while these organoids exhibit microanatomy similar to the authentic brain, they lack proper patterning
along the Anterior-Posterior (AP) and Dorsal-Ventral (DV) axes and interactions with surrounding non-neural
tissues that modulate their development and function. Thus, the neural organoids developed, to date, are unable
to get input from sensory organs and disseminate signals to the rest of the body. Therefore, they cannot mimic
a fully functional nervous system, strongly limiting their use. We seek to rectify this deficiency by building an in
vitro embryo-mimetic system that contains a fully patterned neural tube, capable of receiving signals, and
relaying them systemically. Our strategy is to initiate embryonic development in aggregates of mouse or human
embryonic stem cells (ESCs), instructed with a spatially restricted morphogen activity center, which secretes
WNT and NODAL and acts as an organizer. Our preliminary studies with murine ESCs show that these instructed
aggregates develop into “embryoids” that gastrulate and form all three germ layers. Amongst them, 1/5 are
patterned along AP and DV axes and are bilaterally symmetrical. These embryoids also contain a neural plate
made of columnar neuroepithelial cells that progressively folds into a neural tube. While hindbrain and spinal
cord are present, the embryoids lack the anterior most part of the brain, forebrain and midbrain. We hypothesize
that the lack of anterior brain domains results from an excess of instructive signaling by the posteriorizing factors,
and that correcting this problem will optimize this model for the study of normal and pathological neural
development. In Aim 1, we will further define the cellular composition and spatio-temporal molecular anatomy of
the developing nervous system of bilaterally symmetrical embryoids using high throughput single-cell
transcriptome profiling, as well as tissue specific molecular markers. In Aim 2, we will promote formation of
anterior brain domains by counteracting the potent gradient of posteriorizing factors WNT and NODAL secreted
by the organizing center. Finally, in Aim 3, we will extend our study by producing and analyzing embryoids
containing a neural plate that may fold into a neural tube, from human ESCs. For ethical reasons we will not
attempt at producing the anterior brain domain to avoid the creation in vitro of a human organismal. Altogether,
successful completion of these studies will establish robust in vitro models to study formation and function of the
mammalian ne...

## Key facts

- **NIH application ID:** 10267332
- **Project number:** 1R01NS122723-01
- **Recipient organization:** UNIVERSITY OF VIRGINIA
- **Principal Investigator:** Bernard Victor Thisse
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $399,144
- **Award type:** 1
- **Project period:** 2021-08-01 → 2022-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10267332

## Citation

> US National Institutes of Health, RePORTER application 10267332, In vitro modeling of a mammalian embryonic neural tube (1R01NS122723-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10267332. Licensed CC0.

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