HtrA4 is well conserved only in higher primates and functionally important for EVT differentiation

Area of Science:

• Reproductive Biology
• Developmental Biology
• Biochemistry

Background:

• Deep extra-villous trophoblast (EVT) invasion is a hallmark of human placentation.
• Aberrant expression of serine protease HtrA4 in human placentas is linked to preeclampsia.
• The precise role and evolutionary conservation of HtrA4 in placentation remain largely unknown.

Purpose of the Study:

• To investigate the evolutionary conservation of HtrA4.
• To determine the cellular localization and expression patterns of HtrA4 in different species' placentas.
• To elucidate the functional significance of HtrA4 in human EVT differentiation.

Main Methods:

• Comparative analysis of HtrA4 protein sequences across over 100 species.
• Characterization of HtrA4 in human, rhesus macaque, and mouse placentas, including cellular localization.
• Functional studies using human trophoblast stem cells (TSCs) to assess HtrA4's role in EVT differentiation, including knockdown experiments.

Main Results:

• HtrA4 is highly conserved in higher primates but shows limited conservation in other species.
• Human and rhesus macaque placentas express HtrA4 in trophoblast lineages, while mice do not show significant expression.
• Knockdown of HtrA4 in human TSCs severely inhibited EVT differentiation, indicating its critical role.

Conclusions:

• HtrA4 expression is specific to primate placentas and is essential for human EVT differentiation.
• HtrA4 is a key protease for human placentation, alongside its previously established role in syncytialization.
• These findings underscore HtrA4's importance in the unique aspects of human placental development.