# Mechanisms of Neuronal Temporal Fate

> **NIH NIH R01** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2024 · $537,754

## Abstract

Temporal patterning is an evolutionarily conserved means to generate the proper complement of neurons during
brain development. Our long-term goals are to resolve temporal fate specification in the Drosophila brain and
discern which mechanisms are evolutionarily conserved in mammals. Temporal patterning has been best studied
in Drosophila, where temporal features of the cycling neural stem cells (NSC) are passed to the progeny. Despite
decades of study on temporal pattering of the mouse neocortex, the mechanisms that drive temporal progression
of cortical fates are not well understood. The Drosophila model system is a proven source for fundamental gene
and mechanistic discovery and many aspects of brain development and NSC behavior are conserved between
flies and mammals. Thus, investigating Drosophila temporal factors is a fitting strategy to discover candidates
for mammalian study. Insulin-like growth factor 2 mRNA-binding proteins (IMP) are expressed in fly and mouse
NSCs in a descending temporal gradient. By binding mRNA targets and regulating their protein levels, Drosophila
Imp (together with another RNA binding protein, Syp) controls both neuronal temporal fate and the cycling and
termination of NSCs. Mouse IMP1 and IMP2 similarly regulate temporal changes in NSC behavior. Nonetheless,
a role for IMPs in neuronal temporal fating has not been explored in the mouse. The objectives of this proposal
are to 1) utilize the Drosophila model system to gain deeper insight into temporal fating and 2) explore roles for
mouse IMPs in neocortical neuronal temporal fating. This proposal combines discovery science and targeted
experiments to achieve an in-depth understanding of fating mechanisms at the single-cell level. Specific Aim 1
will uncover the detailed molecular, genetic signatures of a diverse Drosophila neuronal lineage. The
developmental code of neurons as they undergo temporal-fate specification will be matched with the resulting
terminal code. Specific Aim 2 will explore how Imp/Syp temporal gradients and periodic Notch signaling
coordinate to produce terminal neuron fates. Aims 1 & 2 exploit innovative, sophisticated genetic tools to target
a specific neuronal lineage for single-cell RNAseq, reporter-based birth-order analysis, spatial transcriptomics,
and targeted genetic perturbations. Specific Aim 3 will explore mouse IMPs in neocortical neuronal temporal
fating and test the hypothesis that, like Drosophila Imp, mouse IMPs control temporal fate. Aim 3 exploits spatial
transcriptomics to elucidate temporal changes occurring in neocortical progenitors. To test the functions of IMPs,
in-utero electroporation will allow TEMPO (a tool that tracks lineage and birth order) and IMP overexpression
constructs to be expressed in the neocortical progenitors. Our results will help lay the foundation to tailor
neurogenesis, critical for cell-replacement therapies to treat neurological disorders. Moreover, as IMPs are
implicated in other stem cells an...

## Key facts

- **NIH application ID:** 10980826
- **Project number:** 1R01NS134890-01A1
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** TZUMIN LEE
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $537,754
- **Award type:** 1
- **Project period:** 2024-07-01 → 2029-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10980826

## Citation

> US National Institutes of Health, RePORTER application 10980826, Mechanisms of Neuronal Temporal Fate (1R01NS134890-01A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10980826. Licensed CC0.

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