Compound Heterozygosity for Y Box Proteins Causes Sterility Due to Loss of Translational Repression

Area of Science:

• Molecular Biology
• Developmental Biology
• Genetics

Background:

• Y-box proteins YBX2 and YBX3 bind RNA and DNA, playing roles in metazoan development and fertility.
• Functional redundancy between YBX2 and YBX3 has hindered understanding of their roles as RNA masking proteins and identification of target RNAs.

Purpose of the Study:

• To investigate the functional redundancy between YBX2 and YBX3.
• To elucidate the molecular functions of YBX2 and YBX3 in RNA masking and translational regulation.

Main Methods:

• Generation of Ybx3-/- knockout mice and Ybx2-/-;Ybx3-/- double mutants.
• RNA sequencing analysis of messenger ribonucleoprotein (mRNP) and polysome occupancy in heterozygous and homozygous mutants.
• Analysis of spermatid differentiation and male fertility.

Main Results:

• Loss of YBX3 led to reduced male fertility and spermatid differentiation defects.
• Homozygous Ybx2-/-;Ybx3-/- double mutants could not be generated due to sterility in compound heterozygotes, characterized by severe spermatid differentiation defects.
• RNA sequencing revealed a loss of translational repression predominantly in compound Ybx2/3 heterozygotes.
• Y-box protein dose-dependent loss of translational regulation correlated inversely with the presence of Y-box recognition target sequences.

Conclusions:

• YBX2 and YBX3 exhibit functional redundancy, with haploinsufficiency of both leading to sterility and defects in spermatid differentiation.
• Y-box proteins function hierarchically to modulate translation of a range of target RNAs in a dose-dependent manner.
• These findings highlight the critical role of Y-box proteins in male fertility and translational control.