Special AT-rich binding protein-2 (SATB2) differentially affects disease-causing p63 mutant proteins

Area of Science:

• Developmental Biology
• Genetics
• Molecular Biology

Background:

• p63, a p53 family member, is crucial for ectodermal development, including skin, limbs, and craniofacial structures.
• Mutations in p63 cause developmental syndromes like AEC and EEC, often associated with orofacial clefting.
• The differential impact of AEC versus EEC p63 mutations on protein function and interactions remains largely unknown.

Purpose of the Study:

• To investigate the molecular mechanisms underlying differential p63 mutation effects in craniofacial development.
• To identify p63 protein interaction partners involved in craniofacial patterning.
• To elucidate how AEC and EEC-associated p63 mutations affect interactions with SATB2 and downstream gene regulation.

Main Methods:

• Investigated p63 protein interactions with SATB2 in the context of AEC and EEC mutations.
• Analyzed co-expression patterns of p63 and SATB2 during embryonic development.
• Assessed the impact of SATB2 on p63-mediated transactivation of the perp gene promoter.

Main Results:

• AEC-associated p63 mutations impair the interaction between p63 and SATB2.
• p63 and SATB2 are co-expressed in key craniofacial development sites (branchial arches).
• SATB2 inhibits p63-mediated perp gene expression, with this inhibition being more pronounced for AEC p63 mutants.

Conclusions:

• AEC-causing p63 mutations exhibit a novel gain-of-function by altering SATB2 interaction.
• SATB2 is identified as the first p63 binding partner that differentially affects AEC and EEC p63 mutant proteins.
• These findings provide new insights into the molecular basis of orofacial clefting in p63-associated syndromes.