# Mesenchymal-neuroepithelial interactions in the developing telencephalon.

> **NIH NIH R01** · UNIVERSITY OF TENNESSEE HEALTH SCI CTR · 2020 · $332,604

## Abstract

The cerebral cortex is the substrate of human mental prowess. It is believed that its increase in size, with
gyrification and expansion of upper layer neurons, mediates the growth of intellectual capacity during
mammalian evolution. Species-specific cortical cytoarchitecture is largely determined during embryogenesis,
integrating both cell autonomous and non-autonomous mechanisms. We are just beginning to understand the
mechanisms regulating cortical size and gyrification, with contribution of specific secreted molecules into
development of these cortical characteristics being particularly understudied. During development, the cerebral
cortex arises in the telencephalon, lateral to the telencephalic dorsal midline. Several signaling centers have
been described in the developing telencephalon, including a mesenchymal derivative meninges and the
telencephalic dorsal midline, subdivided into the choroid plexus (ChP) and cortical hem (CH). In addition to
secreting signaling molecules, the ChP also produces cerebrospinal fluid that nourishes and protects the brain,
while the CH is a major germinal zone in dorsal brain. While analyzing the role of the transcription factors
Lmx1a and Lmx1b, we found that Lmx1a/b double, but not single, mutants have an extraordinary phenotype of
a compromised telencephalic dorsal midline, and expanded, yet layered neocortex with local overgrowths
resembling gyri and an increased number of upper layer neurons. In addition, in Lmx1a/b double mutants, the
segregation of the dorsal midline lineage from more lateral neuroepithelium was severely compromised, with
dorsal midline progenitors aberrantly dispersing into more lateral neuroepithelium, including the neocortex. To
our surprise, we found that Lmx1a and 1b are never expressed in the neocortex nor coexpressed in the
telencephalon. Instead, during development, Lmx1a expression is limited to the ChP and CH while Lmx1b is
expressed in the adjacent head mesenchyme, suggesting that previously unrecognized mesenchymal-dorsal
midline interactions regulate key aspects of the telencephalic development. The goal of this proposal is to
define Lmx1a/b - dependent mesenchymal / neuroepithelial pathways regulating development of the
telencephalic dorsal midline and neocortex. In Aim 1 we will define how Lmx1a and 1b regulate the
telencephalic dorsal midline patterning and CH growth, two poorly understood processes, which are critical for
proper formation of the ChP and CH. In Aim 2 we will identify a new role of dorsal midline signaling in
neocortical gyrification and expansion of upper layer neurons, and define dorsal midline secreted molecules
mediating these processes. In Aim 3 we will define an Lmx1a/b-dependent molecular pathway regulating the
segregation of the dorsal midline lineage from more lateral neuroepithelium and show that this process is
critical to achieve proper cortical size in mice. Our studies will identify novel fundamental mechanisms
regulating telencephalic deve...

## Key facts

- **NIH application ID:** 9948027
- **Project number:** 5R01NS093009-05
- **Recipient organization:** UNIVERSITY OF TENNESSEE HEALTH SCI CTR
- **Principal Investigator:** Viktor Chizhikov
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $332,604
- **Award type:** 5
- **Project period:** 2016-07-01 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9948027

## Citation

> US National Institutes of Health, RePORTER application 9948027, Mesenchymal-neuroepithelial interactions in the developing telencephalon. (5R01NS093009-05). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/9948027. Licensed CC0.

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