# Investigating thrombocytopenia absent radius syndrome during primitive and definitive hematopoiesis using an induced pluripotent stem cell model

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

## Abstract

Thrombocytopenia absent radius (TAR) syndrome is a rare congenital disorder that causes absence of
the radii, reduced numbers of mature megakaryocytes (MKs), and thrombocytopenia. TAR is caused by
mutations in the RBMBA gene, resulting in reduced mRNA expression of RBMBA and levels of its encoded
protein, Y14, in patient platelets. Since Y14 has no known roles in MK biology, it is currently not understood
how deficiencies in this protein contributes to a MK phenotype without affecting other hematopoietic lineages.
Previous studies of Y14 depletion have identified a role for Y14 in apoptosis and cell cycle regulation, but it is
unclear whether this is the mechanism responsible. Both the postnatal emergence of the thrombocytopenia in
TAR and the known differences in MKs derived from primitive or definitive progenitor cells suggest that
definitive MKs may present a more severe phenotype and thus be a more insightful model. By modeling this
disease in vitro using patient-derived induced pluripotent stem cells (iPSCs) and isogenic corrected lines, we
can assess the effects of TAR on pure cell populations to observe lineage- and developmental stage-specific
changes without influence from the compensatory feedback mechanisms that regulate blood cell generation in
vivo. Overall, we hypothesize that Y14 depletion in TAR syndrome impairs maturation of definitive MKs more
severely than primitive MKs through altered cell cycle and apoptosis regulation, and it does not affect the
development of other blood lineages. Aim 1 of this proposal will determine the specific characteristics of MKs
that is altered due to Y14 depletion during primitive and definitive differentiation. Aim 1A will evaluate aspects
of MK maturation and functionality to determine the specific MK phenotype, and Aim 1 B will determine if
reduced Y14 alters apoptosis and cell cycle progression in MKs as a potential mechanism for this phenotype.
Using RNA-seq, we will detect differential expression of genes related to these pathways or identify any novel
targets with the potential to contribute to the MK defect. Aim 2 will address the MK specificity of TAR by
comparing consequences of Y14 depletion in MK differentiation to erythroid and myeloid differentiations. Aim
2A will discern whether the hematopoietic lineages regulate Y14 RNA or protein levels differently. Aim 28 will
use cell proliferation and lineage-specific surface marker expression to detect potential defects in erythroid or
myeloid development. We will also determine whether cell cycle and apoptosis regulation are altered in these
other lineages as well as any additional pathways that are identified in Aim 1 B. This will be the first study to
directly compare the regulation of cell cycle, apoptosis, and MK maturation during primitive and definitive
hematopoiesis and test whether these models have the potential for divergent disease phenotypes. The results
of this study will not only elucidate the mechanism of TAR syndrome in MKs, b...

## Key facts

- **NIH application ID:** 10535333
- **Project number:** 1F31HL165833-01
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Catriana Nations
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $46,752
- **Award type:** 1
- **Project period:** 2022-09-01 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10535333

## Citation

> US National Institutes of Health, RePORTER application 10535333, Investigating thrombocytopenia absent radius syndrome during primitive and definitive hematopoiesis using an induced pluripotent stem cell model (1F31HL165833-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10535333. Licensed CC0.

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