# Regulation of developmental signaling pathways by glycosylation and deglycosylation

> **NIH NIH R35** · BAYLOR COLLEGE OF MEDICINE · 2022 · $396,252

## Abstract

The majority of secreted and cell-surface proteins of all cell types studied so far are glycosylated, i.e.
decorated with sugar molecules. These carbohydrate modifications play diverse structural and functional roles
in organisms, and are involved in proper animal development and physiology. Mutations in various
components of the glycosylation machinery have been shown to cause more than 100 human diseases,
affecting virtually all organ systems. However, the glycan structures found on animal proteins are complex and
heterogeneous, and each form of glycosylation can be found on tens to thousands of proteins. Therefore, it is
difficult to understand the molecular mechanisms underlying the phenotypes observed in glycosylation
disorders. The long-term goals of our research are to understand how carbohydrate modifications regulate
animal development, to use this knowledge to provide insight into the pathophysiology of human glycosylation
disorders, and to establish frameworks for novel therapeutic approaches in diseases caused or impacted by
mutations affecting protein glycosylation. Our primary area of interest is the intersection between glycobiology
and developmental signaling pathways, which are a small number of evolutionarily conserved, intercellular
signaling mechanisms broadly used during embryonic development and adult maintenance of animals. One
major focus of our research is on O-linked glycans attached to Notch proteins, which constitute the receptors
for one of the most important developmental signaling pathways in animals. We have previously characterized
the role of the enzymes involved in the addition of xylose-glycose-O glycans in the regulation of Drosophila
development and Notch signaling. We have also studied the role of the first enzyme in this pathway
(POGLUT1) in mice, and have linked POGLUT1 to two human diseases, a developmental disorder and a
muscular dystrophy. In the current application, we propose to characterize the role of the enzymes
downstream of POGLUT1 in mammalian development and Notch signaling. Moreover, we have found that an
enzyme involved in removing N-linked glycans from proteins regulates another major signaling pathway (the
bone morphogenetic protein or BMP pathway) in flies in a tissue-specific manner. Mutations in this enzyme
(NGLY1) cause a multi-system developmental disorder in human patients, but the pathophysiology of the
disease is not known. We propose to determine the molecular mechanisms underlying the regulation of the
BMP pathway by NGLY1 in flies, and to determine which aspects of mammalian BMP signaling are regulated
by this enzyme. In addition to providing insight into the roles of glycosylation in the regulation of major signaling
pathways, these projects have the potential to establish novel tools to alter the activity of Notch and BMP
signaling in disease contexts and in regenerative medicine.

## Key facts

- **NIH application ID:** 10330541
- **Project number:** 5R35GM130317-04
- **Recipient organization:** BAYLOR COLLEGE OF MEDICINE
- **Principal Investigator:** Hamed Jafar-Nejad
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $396,252
- **Award type:** 5
- **Project period:** 2019-02-01 → 2024-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10330541

## Citation

> US National Institutes of Health, RePORTER application 10330541, Regulation of developmental signaling pathways by glycosylation and deglycosylation (5R35GM130317-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10330541. Licensed CC0.

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