# (PQ1) Molecular circuit of multi-ciliogenesis regulates choroid plexus differentiation and tumor development

> **NIH NIH R01** · NEW YORK INST OF TECHNOLOGY · 2021 · $350,889

## Abstract

Project Abstract
Neoplasms of the choroid plexus (CP) are rare primary brain tumors predominantly found in childhood. CP
tumors range from the more common and benign
CP papilloma (CPP),
to the rare
CP carcinoma (CPC) that is
poorly understood but highly lethal. Treatments for CPC include surgery, radiation, and chemotherapy that
cause severe long term side effects in survivors. Development of more effective and less debilitating therapies
for CPC has been hampered by limited knowledge of the role of specific molecular defects, including abnormal
NOTCH signaling and recurrent genomic alterations, in CPC. Insights into how these genes and pathways
affect proliferation and growth of CPC will lead to targets for new therapies that can specifically suppress tumor
growth without deleterious effects on the developing brain. By inducing sustained NOTCH1 expression, we
developed mouse models of CP tumor that recapitulate CPP in humans. Lineage studies revealed that
NOTCH-induced CPP originates from roof plate progenitors, both of which exhibit active NOTCH signaling and
undergo proliferation driven by Sonic Hedgehog (SHH) from CP epithelium. In contrast, CP epithelial cells with
clustered multiple primary cilia on the apical surface fail to respond to SHH, suggesting that the NOTCH
pathway suppresses multi-ciliogenesis to preserve the singular primary cilium critical for the SHH signaling.
Though key genes of the multi-ciliation network driven by Geminin coiled-coil domain-containing protein 1
(GEMC1) are expressed in CP epithelium, the transcriptional program is suppressed in NOTCH-activated CPP
that lacks multi-ciliated cells. Conversely, GEMC1 loss results in the lack of multi-ciliation in the CP. In Aim 1,
we will investigate GEMC1-directed multi-ciliate differentiation during CP development and tumorigenesis. We
will determine whether activation of GEMC1 transcriptional cascade is sufficient to overcome constitutive
NOTCH signaling to induce multi-ciliogenesis, and attenuate SHH signaling in CP tumor. Functional studies of
GEMC1 and identification of its transcriptional targets will establish the molecular mechanisms of multi-ciliation
in the CP, and uncover potential therapeutic venues for CP tumor. Consistent with abnormal SHH and NOTCH
signaling in CP tumor in humans, simultaneous activation of both pathways in mice leads to malignant CP
tumors that exhibit solitary primary cilium. Similarly, CPCs in humans are characterized by singular primary
cilium and recurrent genomic alterations affecting crucial regulators of multi-ciliate differentiation. In Aim 2, we
will utilize novel mouse models to investigate the molecular mechanisms of the genetic interaction between the
NOTCH and SHH pathways and evaluate potential targeted therapeutics. We will determine whether the loss
of GEMC1 drives CPC in collaboration with constitutive SHH signaling. The proposed studies will significantly
advance our understanding of CPC and identify potential therapeutic ta...

## Key facts

- **NIH application ID:** 10228589
- **Project number:** 5R01CA220551-06
- **Recipient organization:** NEW YORK INST OF TECHNOLOGY
- **Principal Investigator:** Haotian Zhao
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $350,889
- **Award type:** 5
- **Project period:** 2017-09-01 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10228589

## Citation

> US National Institutes of Health, RePORTER application 10228589, (PQ1) Molecular circuit of multi-ciliogenesis regulates choroid plexus differentiation and tumor development (5R01CA220551-06). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10228589. Licensed CC0.

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