Macrophage-induced immunomodulation in oral tissue repair and regeneration: Recent advances and future perspectives.

Myhre syndrome is an autosomal dominant disorder due to missense mutations that lead to a gain of function in the SMAD4 (Mothers Against Decapentaplegic Homolog 4) protein. This syndrome results from specific recurrent pathogenic variants, with approximately 50% of cases attributed to the p.Ile500Val mutation, 40% to p.Arg496Cys, and less commonly to p.Ile500 mutations involving Threonine, Methionine, or Leucine (; ). Other mutations in the gene, which lead to a loss of function of the protein, cause Juvenile Polyposis/Hereditary Hemorrhagic Telangiectasia syndrome (JP-HHT) (MIM#175050) or predispose individuals to proliferative diseases like gastrointestinal polyps, colorectal, or pancreatic cancers (; ). Myhre Syndrome was first described by Selma A. Myhre in 1981 as “a new syndrome characterized by growth and mental deficiency, unusual facies, hearing loss, generalized muscular hypertrophy, joint limitations and skeletal deformities” (). Thirty years later, research teams led by Dr. Cormier-Daire and Dr. Tartaglia (; ) established the causal relationship between Myhre syndrome and specific SMAD4 pathogenic variants. More recent studies have demonstrated that the most representative SMAD4 variants confer a gain-of-function effect, likely mediated through enhanced stabilization of SMAD complexes and increased protein–protein interactions (). These mechanistic insights are further elaborated in the “MSF portfolio” section, which details the contributions of Dr. Macia’s and Dr. Mo’s laboratories. SMAD4 is a key component of the canonical TGF-β signaling pathway. SMAD proteins are transcription factors whose functional activity is triggered by various stimuli, integrating multiple signaling pathways. SMAD4 functions as a cofactor that, together with receptor-activated SMADs, forms heterotrimeric complexes, either with SMAD1/5/8 or with SMAD2/3. These complexes, once in the nucleus, interact with specific DNA motifs via the MH1 domain (; ; ; ). SMAD4 interacts with several transcription co-factors that determine the specificity of the SMAD complex for enhancers and promoters as well as tissue-specific gene transcription (; ; ; ). SMAD4 also interacts with transcription factors from the Wnt/−β catenin pathway and engages in crosstalk with the NF-kB and Notch pathways (; ). For example, demonstrated that SMAD4 is involved in intracellular integration with the Wnt-β catenin pathway via the formation of a complex with TCF/LEF-1 and β-catenin that binds to DNA and modulates gene transcription. This pathway influences the growth, survival, and differentiation of mesenchymal stem cells (MSCs) and interacts with different players of bone metabolism. Another novel crosstalk discovered by Massagué and coworkers is the interaction between the RAS and TGF-β pathways through the SMAD complex with Ras Responsive Binding Element 1 (RREB1) and the chromatin remodeler INO80 complex, which triggers fibrogenic and developmental epithelial-to-mesenchymal transition (EMT) (; ). SMAD4 is downstream in the canonical pathways of all receptors of the broader TGF-β superfamily, including 12 receptors and 33 ligands, and several coreceptors such as endoglin (). Therefore, it triggers a functional cellular response of high diversity in a cell type dependent manner. TGF-β superfamily pathways are involved in critical processes such as development, growth, immunity, and homeostasis, from embryonic stages to elderly stages. Dysregulation of SMAD4 is linked to various developmental disorders, including defects in skeletal muscle differentiation and regeneration, loss of stem cell pluripotency, developmental defects in the central and peripheral nervous system, and female infertility (). These findings help explain why gain-of-function mutations in SMAD4 cause disruptions in the cellular functions of multiple tissues, including connective, neuronal, and muscular tissues, as well as the liver and reproductive systems. Related to Myhre syndrome considering a gain of function, the SMAD4-dependent response to the Anti-Mullerian Hormone Receptor II stimulation would trigger an alteration of sexual hormones and early puberty, defects in bones, and autism spectrum disorder (), while the activin and Nodal will interfere with embryonic development (, ), BMPs with bone development, the immune system, and cellular proliferation. TGF-β plays a central role in fibrosis by activating signaling pathways that promote extracellular matrix (ECM) production, myofibroblast differentiation, and inflammation ().