The mammalian epidermis forms a critical barrier against environmental insults and water loss. The formation of its outermost layer, the stratum corneum, involves a rapid terminal differentiation process that has traditionally been explained by the "bricks and mortar" model. Recent advances reveal a more dynamic mechanism governed by intracellular liquid-liquid phase separation (LLPS). This review proposes that the lifecycle of the granular layer is orchestrated by LLPS. Evidence is synthesized showing that keratohyalin granules (KGs) are biomolecular condensates formed by the phase separation of the intrinsically disordered protein filaggrin (FLG). The assembly, maturation, and pH-triggered dissolution of these condensates are essential for cytoplasmic remodeling and the programmed flattening of keratinocytes, a process known as corneoptosis. In parallel, an LLPS-based signaling pathway is described in which the kinase RIPK4 forms condensates that activate the Hippo pathway, promoting transcriptional reprogramming and differentiation. Together, these structural and signaling condensates drive skin barrier formation. This review further reinterprets atopic dermatitis, ichthyosis vulgaris, and Bartsocas-Papas syndrome as diseases of aberrant phase behavior, in which pathogenic mutations alter condensate formation or material properties. This integrative framework offers new insight into skin biology and suggests novel opportunities for therapeutic intervention through biophysics-informed biomaterial and regenerative design.

Human RIPK4 mutation leads to Bartsocas-Papas syndrome (BPS), characterized by severe skin, craniofacial and limb abnormalities. Currently, our understanding of RIPK4's function has focused on epidermal differentiation and development, whether RIPK4 regulates skeletal homeostasis remains largely elusive. Herein, through global RIPK4 ablation in adult mice, we demonstrate that RIPK4 deficiency leads to osteoporosis, promotes myeloid-biased hematopoiesis and osteolineage RIPK4 plays a crucial role in bone formation and myeloid hematopoiesis. Further detailed investigation pinpoints that RIPK4 interacts with mitochondrial fusion protein MFN2 in a kinase-dependent manner. RIPK4 facilitates the phosphorylation of MFN2, which subsequently undergoes degradation through the proteasome pathway and disrupts the dynamic equilibrium of mitochondrial fission and fusion. Additionally, we also show that osteolineage RIPK4 maintains bone marrow myelopoiesis by MFN2-mediated mitochondrial transfer. More interestingly, while osteocytic RIPK4 could modestly influence the osteogenesis, it is insufficient to sustain bone marrow myelopoiesis owing to the limited amount of mitochondria transfer. These findings decipher the essential role of RIPK4 in maintaining skeletal homeostasis and unveil an unappreciated mechanism of RIPK4-MFN2 axis in regulating osteogenesis and bone marrow myelopoiesis.

Proteins which regulate morphogenesis of the epidermis ensure its proper construction and function and mutations or abnormal expression of those proteins impact epidermal function. One recently described protein is Receptor Interacting Serine/Threonine Kinase 4 (RIPK4). Mutations in RIPK4 cause the autosomal-recessive form of Bartsocas-Papas syndrome and Popliteal Pterygium Syndrome the Aslan type. In mice, deletion of Ripk4 (Ripk4-/-) leads to premature death of neonates caused by numerous skin adhesions. RIPK4 regulates development and maintenance of differentiation and proliferation homeostasis of keratinocytes, as well as inflammation. RIPK4 also appears to act as a tumor suppressor in skin, since expression is decreased in squamous skin carcinoma and inducible deletion in mice facilitates induction and growth of papillomas and squamous skin carcinomas in chemical carcinogenesis. The review describes the RIP family, the engagement of RIPK4 in differentiation of the epidermis and consequences resulting from its improper expression. Białka regulujące morfogenezę naskórka zapewniają jego prawidłową budowę oraz funkcję. Mutacje w ich obrębie prowadzą do licznych zaburzeń w pełnionej funkcji. Jednym z takich ostatnio opisanych białek jest kinaza białkowa oddziałująca z receptorem kinaz serynowo-treoninowych 4 (RIPK4). Kinaza ta w naskórku pełni ważną funkcję regulatora homeostazy pomiędzy proliferacją a różnicowaniem się keratynocytów. Mutacje w obrębie genu kodującego białko RIPK4 skutkują u ludzi letalnym zespołem Bartsocas-Papas lub zespołem mnogich płetwistości typu Aslana, a jego delecja u myszy (Ripk4-/-) prowadzi do przedwczesnej śmierci noworodków spowodowanej licznymi zrostami skórnymi. RIPK4 odgrywa rolę w stanie zapalnym skóry. Sugeruje się, że białko to w skórze pełni rolę supresora nowotworów, ponieważ jego poziom zmniejsza się w rakach kolczystokomórkowych względem skóry zdrowej, a jego indukowana delecja w modelu mysim sprzyja powstawaniu i rozrostowi brodawczaków i raków kolczystokomórkowych wywoływanych na drodze chemicznej. W pracy omówiono rodzinę białek RIP, udział białka RIPK4 w różnicowaniu się naskórka i szlakach sygnalizacyjnych, a także konsekwencje zaburzeń wywołanych jego nieprawidłową ekspresją.

Bartsocas-Papas syndrome (BPS) is a rare autosomal recessive disorder characterized by popliteal pterygia, syndactyly, ankyloblepharon, filiform bands between the jaws, cleft lip and palate, and genital malformations. Most of the BPS cases reported to date are fatal either in the prenatal or neonatal period. Causative genetic defects of BPS were mapped on the RIPK4 gene encoding receptor-interacting serine/threonine kinase 4, which is critical for epidermal differentiation and development. RIPK4 variants are associated with a wide range of clinical features ranging from milder ectodermal dysplasia to severe BPS. Here, we evaluated a consanguineous Turkish family, who had two pregnancies with severe multiple malformations compatible with BPS phenotype. In order to identify the underlying genetic defect, direct sequencing of the coding region and exon-intron boundaries of RIPK4 was carried out. A homozygous transversion (c.481G>C) that leads to the substitution of a conserved aspartic acid to histidine (p.Asp161His) in the kinase domain of the protein was detected. Pathogenicity predictions, molecular modeling, and cell-based functional assays showed that Asp161 residue is required for the kinase activity of the protein, which indicates that the identified variant is responsible for the severe BPS phenotype in the family.

Bartsocas-Papas syndrome (BPS) is an autosomal recessive form of Popliteal Pterygium syndrome (PPS). It is a very rare disease characterized by congenital craniofacial anomalies, popliteal webbing, and genitourinary and musculoskeletal anomalies. Almost all of the cases were reported in dead intrauterine pregnancies. We present a 10-month-old boy with bilateral complete cleft lip and palate, abnormal scalp hair, an absence of both upper eyelids, choanal atresia, syndactyly of the third and fourth fingers of the right hand, agenesis fingers on the left hand, bilateral popliteal pterygia, bilateral talipes equinovarus, agenesis of the toes of both lower extremities, intercrural webbing, an absence of testis, and scrotal anomaly. Multistage surgical correction was performed for the multiple congenital malformations. We report the first case of BPS from Indonesia. Gradual management should be performed according to the patient's age and available facilities.