Rbm8a deficiency causes hematopoietic defects by modulating Wnt/PCP signaling

Area of Science:

• Developmental Biology
• Genetics
• Hematology

Background:

• Thrombocytopenia-Absent Radius (TAR) syndrome is a rare genetic disorder characterized by low platelet counts and limb abnormalities.
• Mutations in RBM8A, a component of the exon junction complex, are implicated in TAR syndrome.
• The precise mechanisms by which RBM8A dysfunction leads to specific TAR phenotypes are not fully understood.

Purpose of the Study:

• To investigate the molecular mechanisms underlying TAR syndrome phenotypes in a zebrafish model.
• To explore the role of non-canonical Wnt/Planar Cell Polarity (PCP) signaling in RBM8A-associated developmental defects.
• To identify key developmental pathways affected by reduced RBM8A function.

Main Methods:

• Utilized zebrafish models with hypomorphic or null mutations in the rbm8a gene.
• Analyzed hematopoietic cell populations (cd41-positive thrombocytes).
• Assessed mRNA integrity and intron retention.
• Investigated interactions between rbm8a and non-canonical Wnt/PCP pathway genes (wnt5b, wnt11f2, fzd7a, vangl2).
• Examined the expression of hematopoietic and endothelial genes (runx1, gfi1aa).

Main Results:

• Zebrafish rbm8a perturbation led to reduced thrombocyte counts and accumulation of mRNAs with retained introns.
• Impaired rbm8a function disrupted non-canonical Wnt/PCP signaling, causing convergent extension defects.
• Reduced rbm8a function interacted with PCP pathway gene perturbations, affecting lateral plate mesoderm (LPM) development.
• Mutants exhibited impaired expression of critical hematopoietic/endothelial genes, runx1 and gfi1aa.

Conclusions:

• Aberrant lateral plate mesoderm (LPM) patterning is a key consequence of attenuated non-canonical Wnt/PCP signaling in rbm8a mutants.
• Hematopoietic defects observed in TAR syndrome models are linked to disrupted Wnt/PCP signaling pathways.
• This study provides a mechanistic link between mRNA processing defects and specific developmental abnormalities in TAR syndrome.