# A heterochronic model for birth defects in Down Syndrome

> **NIH NIH R01** · UNIVERSITY OF CHICAGO · 2023 · $5,035,031

## Abstract

PROJECT SUMMARY
The fundamental question for the field of Down Syndrome (DS) basic research is how an extra
copy of human chromosome 21 (HSA21) translates into the organ-specific pathologies that are
observed in the DS population. Structural pathologies in DS, such as brain size and heart
malformation, are present at birth, and are generally associated with smaller organs or reduced
growth. Therefore, they must be causally related to structural organogenesis defects, reflecting
embryologic origins. A mechanistic understanding of DS-specific organogenesis defects is lacking
in most cases, although a rich descriptive literature sets the stage for concerted mechanistic
studies. Specifically, how Trisomy 21 (T21) causes heart or brain morphogenesis defects, causing
CHD or intellectual disability, respectively, is poorly understood. The molecular networks identified
by the proposed work, implicated in DS organ-specific cardiac and neuronal progenitors, will serve
as a template for understanding the molecular ontogeny of heart and brain defects, as well as
other organ defects, in DS. We have defined Hedgehog (Hh) signaling as an explicit development
timer during mammalian development, required for maintaining organ-specific progenitor cells
and dictating their differentiation in time and space, independent from developmental patterning
or proliferation. The controlled balance between organ-specific progenitors and their differentiated
counterparts is fundamental to complex organogenesis. The Moskowitz lab found that when Hh
signaling is abrogated in cardiac progenitors, they underwent precocious differentiation, resulting
in morphogenesis failure. Similarly, the Bhattacharyya lab has recently identified deficits in the Hh
pathway in neuronal progenitors that controls their differentiation. We propose the transformative
hypothesis that a unifying cause of birth defects in DS is failure of heterochronic timing control of
organ-specific progenitor differentiation, resulting in precocious differentiation, a reduction of
organ-specific progenitors, morphogenesis failure and birth defects in multiple organs.

## Key facts

- **NIH application ID:** 10658360
- **Project number:** 1R01HD111938-01
- **Recipient organization:** UNIVERSITY OF CHICAGO
- **Principal Investigator:** Ivan Paul Moskowitz
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $5,035,031
- **Award type:** 1
- **Project period:** 2023-04-01 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10658360

## Citation

> US National Institutes of Health, RePORTER application 10658360, A heterochronic model for birth defects in Down Syndrome (1R01HD111938-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10658360. Licensed CC0.

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