# Restriction of the Zebrafish Dorsal Organizer by Integrator Complex Subunit 6

> **NIH NIH F31** · UNIVERSITY OF PENNSYLVANIA · 2022 · $46,752

## Abstract

Project Summary/Abstract
The vertebrate body axis is specified by an embryonic signaling center called the dorsal organizer. A unique
zebrafish loss-of-function mutant isolated in our laboratory, called ints6p18ahub, promises to provide new insights
into how the organizer is repressed to specify the proper balance of dorsoventral tissues. In this maternal-effect
mutant, the progeny of homozygous ints6p18ahub mutant females (called M-ints6p18ahub embryos) display expanded
organizers and multiple body axes. No other loss-of-function mutation in the zebrafish produces multiple body
axes: therefore, this mutant will likely reveal a new mechanism of dorsal organizer repression. The mutated
gene, Integrator complex subunit 6 (ints6), encodes a member of the Integrator complex, a spliceosomal small
nuclear RNA processing complex that has not previously been implicated in vertebrate embryonic patterning.
The experiments proposed here will uncover the mechanism by which Ints6 represses the dorsal organizer.
Preliminary transcriptomic data support the hypothesis that a newly discovered function of Integrator, called
transcriptional attenuation, represses dorsal gene expression in ventrolateral tissues to repress the organizer.
First (Aim 1), RNA-seq and ChIP-seq will be utilized in M-ints6p18ahub embryos to evaluate Integrator’s five known
biochemical activities in mutant embryos, determining which one is responsible for repressing the organizer.
Second (Aim 2), Integrator’s 13 other subunits will be knocked down in M-ints6p18ahub mutant embryos to
determine which knockdowns enhance the dorsalized phenotype, investigating which other subunits may
participate in dorsal organizer repression by Ints6. Finally (Aim 3), a spatially localized genetic rescue experiment
will be used in M-ints6p18ahub embryos to determine where Ints6 acts to repress the organizer. This will reveal
how the new mechanism of dorsal organizer repression by Ints6 fits into the timeline of known embryonic
patterning events in the zebrafish. In summary, the experiments proposed here will reveal how Ints6, a newly
identified repressor of the dorsal organizer, restricts the organizer’s axis-specifying potential. This proposed
fellowship will be performed in a collaborative and supportive environment to develop the applicant’s scientific
independence and prepare for a career in science. The applicant will be mentored by a supportive thesis mentor
and expert thesis committee.

## Key facts

- **NIH application ID:** 10568987
- **Project number:** 5F31HD106718-02
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** William Douglas Jones
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $46,752
- **Award type:** 5
- **Project period:** 2021-08-02 → 2024-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10568987

## Citation

> US National Institutes of Health, RePORTER application 10568987, Restriction of the Zebrafish Dorsal Organizer by Integrator Complex Subunit 6 (5F31HD106718-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10568987. Licensed CC0.

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