OGT mediates O-GlcNAcylation of MEIS2 and affects palatal osteogenic development

Zhongyin Zhang1,2,3, Zerui Shan1,2,3, Xinyu Chen1,2,3

  • 1Department of Orthodontics, The Affiliated Stomatological Hospital of Nanjing Medical University, Nanjing, China.

Insights

O-linked β-D-N-acetylglucosamine (O-GlcNAc) is crucial for palatal bone development. Reduced O-GlcNAc levels and O-GlcNAcylation of MEIS2 protein contribute to cleft palate, offering new diagnostic and preventive strategies.

Area of Science:

  • Biochemistry
  • Developmental Biology
  • Genetics

Background:

  • Post-translational modifications (PTMs) like O-GlcNAcylation regulate vital cellular processes.
  • Congenital malformations, including cleft palate, are increasingly linked to PTM dysregulation.
  • O-GlcNAcylation plays a role in transcription, translation, and cell fate determination.

Purpose of the Study:

  • To investigate the role of O-GlcNAcylation in palatal development and cleft palate formation.
  • To identify the specific mechanisms by which O-GlcNAcylation influences palatal bone formation.
  • To explore the potential of O-GlcNAc levels as biomarkers or therapeutic targets for cleft palate.

Main Methods:

  • Utilized all-trans retinoic acid (atRA)-induced cleft palate mouse models to assess O-GlcNAc levels.
  • Employed zebrafish models to study the effects of O-GlcNAc deficiency on palatal development.
  • Investigated the interaction between O-GlcNAcylation, MEIS2 protein stability, and ubiquitination pathways.

Main Results:

  • A significant decrease in O-GlcNAc levels was observed in the palatine plates of atRA-induced cleft palate mice.
  • Loss of O-GlcNAc in zebrafish led to increased cleft palate prevalence and impaired palatal bone formation.
  • O-GlcNAcylation of MEIS2 by OGT was found to stabilize the protein by inhibiting ubiquitination, maintaining osteogenic homeostasis.
  • Serine 237 (Ser237) was identified as a key site for MEIS2 O-GlcNAcylation.

Conclusions:

  • O-GlcNAcylation, particularly of MEIS2, is essential for normal palatal bone development.
  • Dysregulation of O-GlcNAcylation contributes to cleft palate pathogenesis.
  • This study provides a novel framework for understanding palatal development regulation and suggests potential avenues for cleft palate diagnosis and prevention.

Related Concept Videos

Oligosaccharide Assembly01:24

Oligosaccharide Assembly

Protein glycosylation starts in the ER lumen and continues in the Golgi apparatus. Glycosyltransferases catalyze the addition of sugar molecules or glycosylation of proteins. Usually, these enzymes add sugars to the hydroxyl groups of selected serine or threonine residues to form O-linked glycans or the amino groups of asparagine residues to form N-linked glycans. Different positions on the same polypeptide chain can contain differently linked glycans.
Multiple sugar molecules that may or may...
3.8K
Proteoglycans01:05

Proteoglycans

Glycans, a class of complex heterogeneous molecules, can be covalently attached to proteins to form glycosylated proteins that regulate various physiological and pathological processes. Glycosylated proteins or glycoproteins comprise N-linked and O-linked oligosaccharides. O-glycosylation is the most common type of protein glycosylation. Here, glycans attach to the oxygen atom of the hydroxyl groups of Serine or Threonine residues. O-linked glycosylation occurs later in protein processing,...
5.2K
Protein Glycosylation01:25

Protein Glycosylation

Glycosylation, the most common post-translational modification for proteins, serves diverse functions. Adding sugars to proteins makes the proteins more resistant to proteolytic digestion. Glycosylated proteins can act as markers and receptors to promote cell-cell adhesion. Additionally, they have many essential quality control functions in the cell, such as correct protein folding and facilitating transport of misfolded proteins to the cytosol, which can be degraded.
Glycosylation occurs in...
10.5K
Glycosaminoglycans01:23

Glycosaminoglycans

Glycosaminoglycans (GAGs), also known as mucopolysaccharides, are long and linear polymers comprising of specific repeating disaccharides - the amino sugar that can be N-acetylglucosamine or N-acetylgalactosamine, and a uronic acid that is usually glucuronic acid or iduronic acid.
GAGS are found in the extracellular matrix of vertebrates, invertebrates, and bacteria. Due to their polar nature they attract water, and serve as excellent lubricants or shock absorbers in an animal body.
Hyaluronic...
7.8K
Bone Formation by Endochondral Ossification01:24

Bone Formation by Endochondral Ossification

Bone formation, or ossification, begins around the sixth to seventh week of embryonic development. Most bones develop from a cartilaginous template through the process of endochondral ossification. Cartilage formation begins when clusters of mesenchymal cells differentiate into chondrocytes. These chondrocytes proliferate rapidly and secrete an extracellular matrix that becomes encased in a membrane called the perichondrium. The resulting cartilage model provides a template that resembles the...
14.5K
Osteoclasts in Bone Remodeling01:31

Osteoclasts in Bone Remodeling

Osteoclasts are cells responsible for bone resorption and remodeling. They originate from hematopoietic progenitor cells present in the bone marrow. Numerous progenitor cells fuse to form multinucleated cells, each with 10-20 nuclei. A single osteoclast has a diameter of 150 to 200 µM. These cells have ruffled borders that break down the underlying bone tissue and release minerals such as calcium into the blood in bone resorption. Osteoclasts cling to bones with their ruffled edges during...
4.8K