# Transcriptional control of Sonic hedgehog signaling

> **NIH NIH R01** · UNIVERSITY OF PENNSYLVANIA · 2022 · $412,488

## Abstract

The spatial arrangement of thalamic nuclei is important for generating the precise topographical relationship
needed to fulfill its role as a relay and information processing center. Despite advances in our understanding of
the early events regulating thalamic growth and regionalization, there remain major gaps in knowledge of the
mechanisms by which heterogeneous clusters of excitatory relay neurons are specified and aggregate into
distinct thalamic nuclei. One particular challenge has been to decipher the full complement of thalamic
progenitor identities and to elucidate their contribution to specific thalamic nuclei. The overarching goal of this
grant proposal is to elucidate the molecular logic underlying the identity of neuronal progenitor sub-types in the
developing thalamus and to gain mechanistic insight into how alterations in their gene regulatory networks
contribute to sensory and motor deficits in neurodevelopmental disorders. One factor in particular, the secreted
morphogen Sonic hedgehog (Shh), has been implicated in spatiotemporal and threshold models of thalamic
development that differ from other areas of the CNS due, in large part, to its expression within two signaling
centers, the basal plate and the zona limitans intrathalamica (ZLI), a dorsally projecting spike that separates
the thalamus from the prethalamic territory. We will employ a top down, phenotype driven, approach to
deconstruct the spatiotemporal role of Sonic hedgehog (Shh) signaling in thalamic development and function.
Mice with mutations in Shh brain enhancers (SBE1 and SBE5) will be leveraged to investigate the effect that
disruption of Shh expression has on the formation of thalamic nuclei using a multiplexed single molecule in situ
method for quantitative analysis of gene expression in individual thalamic cell types. Follow up studies will
examine the impact that these neuroanatomical defects have on thalamic circuit assembly, as well as motor
and sensory behaviors. A parallel, bottom-up approach, will define the genetic programs driving thalamic
progenitor subtype identity and corresponding lineage trajectories using single-cell RNA-seq (scRNA-seq)
profiling of control and SBE1/5-/- mutant embryos over developmental time. Finally, we will also study the
mechanism of enhancer redundancy and the role that SBE1 and SBE5 play in facilitating the three-dimensional
folding dynamics of the Shh locus in the developing brain using a novel super resolution imaging-based
method. Taken together, the conceptual framework of our experimental approach is intended to address
fundamental questions of biological importance in developmental neurobiology using innovative methods with
the added goal of uncovering novel pathogenic mechanisms of neurodevelopmental disease that may inform
future treatment options.

## Key facts

- **NIH application ID:** 10447014
- **Project number:** 5R01NS039421-22
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** DOUGLAS J EPSTEIN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $412,488
- **Award type:** 5
- **Project period:** 2000-03-01 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10447014

## Citation

> US National Institutes of Health, RePORTER application 10447014, Transcriptional control of Sonic hedgehog signaling (5R01NS039421-22). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10447014. Licensed CC0.

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