Molecular determinants for small Maf protein control of platelet production

Area of Science:

• Hematology
• Molecular Biology
• Genetics

Background:

• NF-E2, a heterodimer of MafG and p45, regulates megakaryopoiesis via binding to MARE and activating platelet gene transcription.
• The basic region-leucine zipper (bZip) domain of MafG was previously considered its sole functional domain, essential for p45 binding and transcriptional activation.

Purpose of the Study:

• To investigate the in vivo function of the MafG C-terminal region, distinct from its bZip domain.
• To determine if the MafG C terminus plays a role beyond mediating p45 binding to MARE.

Main Methods:

• Utilized a transgenic complementation rescue assay in mice.
• Generated and analyzed compound mutant mice lacking both functional MafG and expressing a MafG mutant lacking the C terminus (MafGΔC).

Main Results:

• MafGΔC mutant mice on a MafG-null background exhibited severe thrombocytopenia and splenomegaly, mirroring p45-null mice phenotypes.
• The MafG C terminus was found to be essential for proplatelet formation and platelet gene activation.
• The MafG C terminus was not required for p45 binding to the MARE sequence.

Conclusions:

• The C-terminal region of MafG contains a nuclear matrix-targeting signal and is essential for NF-E2 function in vivo.
• Efficient targeting of NF-E2 to nuclear scaffolds is critical for achieving high-level transcriptional activity in megakaryopoiesis.