Regulators of the proteasome pathway, Uch37 and Rpn13, play distinct roles in mouse development

Area of Science:

• Cell Biology
• Developmental Biology
• Genetics

Background:

• Rpn13 is a novel mammalian proteasomal receptor and an amplification target in ovarian cancer.
• Rpn13 interacts with ubiquitin and activates Uch37, a deubiquitinating enzyme, at the 26S proteasome.
• Neither Rpn13 nor Uch37 are integral proteasomal subunits, prompting investigation into their essentiality for mammalian development.

Purpose of the Study:

• To investigate the physiological roles of Uch37 and Rpn13 in mammalian development and survival.
• To determine the impact of Rpn13 and Uch37 deficiency on proteasomal function and organismal health.
• To explore the potential link between Rpn13 and gametogenesis.

Main Methods:

• Generation of Uch37 and Rpn13 knockout mice.
• Assessment of embryonic lethality and developmental defects.
• Analysis of proteasome activity in various tissues.
• Evaluation of body composition, fertility, immune cell counts, and hormone levels in adult mice.

Main Results:

• Uch37 deletion resulted in prenatal lethality with severe embryonic brain defects.
• Rpn13-deficient mice survived to adulthood but exhibited smaller size at birth and reduced numbers.
• Absence of Rpn13 led to tissue-specific alterations in proteasome activity, infertility, increased body fat, elevated T-cell numbers, and altered growth hormone and FSH levels.

Conclusions:

• Uch37 is essential for embryonic development, particularly brain development.
• Rpn13 plays a critical role in mammalian development, survival, and gametogenesis.
• This study implicates Rpn13, a non-ATPase proteasomal protein, in the regulation of gametogenesis and highlights its broader physiological functions.