Every face is unique. Our features are largely inherited, but sometimes errors occur in genes that disrupt the precise "assembly" of facial tissues early in pregnancy. This results in craniofacial differences such as cleft lip (cleft of the upper lip) and/or palate. If not treated in a timely and interdisciplinary manner, such conditions can strongly impact a child's quality of life – from breathing and feeding, through hearing and speech development, to vision and frequent ear infections.
How the face forms and why clefts occur
In the first weeks of pregnancy, tiny "protrusions" of the embryo – the maxillary, medial, and lateral nasal processes – grow, move closer, and must precisely join together. This junction is often described as closing a "zipper". When this process is disrupted, a cleft occurs. A cleft lip marks the separation of the two sides of the upper lip (often including the alveolar ridge and premaxilla), while a cleft palate is an opening in the roof of the mouth, which can affect the hard and/or soft palate.
Clefts are among the most common congenital differences. Public health agency data state that in the United States, approximately one in 1,050 newborns is born with a cleft lip with or without a cleft palate, and about one in 1,600 with an isolated cleft palate. More broadly, structural congenital differences affect about one in 33 children. These data are important because they direct the health system toward early diagnosis and team-based treatment.
What science sees "live" today: a laboratory watching how the lip forms
In the laboratory at the University of California, San Francisco (UCSF) led by Prof. Jeffrey Bush, PhD, researchers have been studying for years how the human face is shaped in utero. His team – students, postdocs, and technicians – investigates the molecular and cellular steps that lead to the creation of a healthy face, but also the places where the process can go wrong. They specifically monitor the development of the upper lip and palate, as cleft lip and cleft palate are among the most common congenital facial malformations.
A key breakthrough in recent years has been the introduction of advanced live imaging: live mouse embryos recorded over time, frame by frame. Such recordings reveal how neighboring cell populations move, "grab," and fuse into a continuous lip contour. In combination with precise genetic tools (CRISPR-Cas9) that allow a version of a gene seen in patients to be intentionally introduced into an animal model, researchers can observe exactly at which moment and in what way the "zipper" stops closing – and what the consequence is.
A small force making a big difference: the actomyosin "towing apparatus" and glue between cells
The latest research from Bush's team in the Journal of Cell Biology shows that the edges of the future lip attract and join thanks to finely regulated forces of the actomyosin system – a kind of internal "ropes" with which cells develop tension and pull tissues toward each other. However, for that contact to turn into a permanent bond, cells also need to adhere firmly enough. This role is played by cadherins – protein "adhesives" on their surface. The study suggests that successful fusion requires a certain, threshold-defined stability of cadherin connections; if it is below the threshold, the tissue does not fuse and a cleft occurs.
Within this family of adhesive proteins, P-cadherin (a protein encoded by the CDH3 gene) plays an important role. In the context of epithelial development and tissue modeling, its proper dosage and positioning are crucial for young tissues to "stick" correctly. Although P-cadherin is well known in ophthalmologic and dermatologic syndromes, there is increasing evidence that disorders in its regulation and cooperation with other cadherins can contribute to the formation of cleft lip in a portion of patients. Additionally, p120-catenin – a regulator that protects cadherins from degradation and stabilizes their junctions – proves to be a key "guardian" of that adhesion. In experimental conditions where p120-catenin function is impaired, cadherins are lost from the cell surface faster, and fusion fails.
Genes, environment, and time: where risks overlap
A cleft occurs when multiple factors coincide at a bad moment: a genetic variant that changes protein function, environmental stress (e.g., smoking during pregnancy) or nutritional deficit, and a critical window of development. That is precisely why preventive measures – cessation of smoking, adequate intake of folic acid, and early prenatal care – remain the first line of public health protection.
At the same time, genetic insights help explain why two pregnant women with seemingly identical habits do not carry the same risk. Bush's laboratory systematically models gene changes observed in families with clefts: using CRISPR, these changes are "copied" into a mouse, and then, with live imaging, it is monitored how this affects cell movement, actomyosin fiber tension, and adhesion strength. Such an approach allows for translating a genetic variant into an actual disease mechanism, step by step.
What doctors can do today, and what tomorrow promises
In clinical practice, clefts are most often recognized by ultrasound in the second trimester (around weeks 18–22), when it is possible to plan the birth and early interventions in experienced centers. Advanced 3D and 4D techniques, as well as specific orientation sections, allow for earlier or more detailed assessment in certain cases. Diagnostics and care are carried out by a team – including pediatrics, maxillofacial and plastic surgery, otorhinolaryngology, audiology, speech therapy, orthodontics, psychology, and other professions. Professional association guidelines emphasize the importance of a coordinated team approach from birth to the completion of growth, with clearly defined roles and a plan for monitoring hearing, speech, dental and skeletal development, and psychosocial support.
Surgical corrections remain the foundation of treatment. It is common for primary correction of the cleft lip to be planned during the first months of life, while the palate is reconstructed at an age optimal for speech development according to the chosen center protocol. If necessary, additional procedures follow: orthodontic preparation, alveolar bone graft, secondary corrections of the nose and lip, as well as speech and audiological rehabilitation. Protocols are implemented worldwide which, while sharing the same goals (feeding, speech, hearing, facial growth), choose different time points and techniques, and there is an increasing emphasis on outcome measurement and long-term follow-up.
Nevertheless, the vision of researchers goes beyond the scalpel. Understanding cellular biomechanics and adhesion opens the possibility of developmental "microtherapies" with which, one day, forces and signaling pathways could be modulated in high-risk pregnancies so that the disrupted "zipper" closes after all. This does not mean that such prenatal therapy is within reach today – it is not yet – but the mechanistic roadmap created by researchers like Bush's team is the first prerequisite for such approaches to be tested one day.
Why funding and collaboration are key
Basic research of this kind is expensive and long-term. Bush's laboratory is primarily funded through the US National Institutes of Health (NIH), specifically via the National Institute of Dental and Craniofacial Research (NIDCR). Such funds allow for the acquisition and development of advanced microscope systems, breeding of transgenic animals, recombinant gene-editing tools, and the employment of specialized experts for data analysis. The result consists of publications in leading journals and a practicum of knowledge that can be quickly "translated" toward clinical application.
From the lab to the baby: the path to a better outcome
When insights from the laboratory are placed into the broader framework of healthcare, we gain three key benefits. First, more precise prenatal diagnostics: knowledge of where and when tissues break or fail to fuse directs the execution of targeted sections and interpretation of findings. Second, better parental counseling: understanding the mechanism helps to realistically explain why the cleft occurred and what can be expected, and even what the probability of recurrence is in the next pregnancy. Third, data-driven protocols: consistent collection and comparison of outcomes allow centers to adapt their procedures to evidence – from the age of palatoplasty to hearing and speech rehabilitation strategies.
For families, it is most important to know that early involvement of a multidisciplinary team brings measurable benefits – both functionally and psychosocially. Due to the risk of middle ear effusions and conductive hearing loss, regular audiological control and, if necessary, the insertion of ventilation tubes are often part of the plan. Speech therapy support starts early, and an orthodontist and maxillofacial surgeon monitor the growth and development of teeth and the upper jaw. In some centers, nasoalveolar molding (NAM) in the first weeks of life improves soft tissue symmetry and facilitates later reconstructions; in selected cases, alveolar bone grafting supported by recombinant growth factors shows promising results but requires strict selection and specialist supervision.
What new biology tells us about tomorrow's therapies
At the core of newer papers lies the idea of an adhesion threshold: adhesive proteins must reach a critical level of stability and distribution for the lip to close. p120-catenin acts here as a "guardian" of cadherins – if its function is insufficient, cadherins leave the membrane faster and the bond gives way. In parallel, the actomyosin apparatus generates tensile forces that bring tissue edges into contact. Pharmacological weakening of that apparatus in a model leads to non-fusion, which directly demonstrates the causality of mechanical forces in morphogenesis. This combination of "towing" and "glue" seems to be the minimal condition for proper fusion; when one element weakens, the other cannot fully replace it.
The CDH3 gene, which encodes P-cadherin, is an additional link. Although CDH3 mutations are classically associated with rare skin and retinal syndromes, papers in developmental models show its important role in epithelial morphogenesis. Establishing the correct place and time of P-cadherin expression, its cooperation with E- and other cadherins, and stabilization via p120-catenin together determine whether the edges of the future lip will join firmly.
Responsible use of new technologies
In this story, CRISPR is a tool for understanding, not for clinical application. In animal models, it allows for the precise introduction of a gene alteration carried by individual patients or families and tracking the consequence at the level of the cell, tissue, and ultimately, morphology. Such information complements patient sequencing and systematic biobanks and enables distinguishing a benign variant from a pathogenic one. However, before anything similar could be considered as treatment during pregnancy, numerous ethical, safety, and regulatory issues would have to be resolved; for now, the focus is on mapping mechanisms and identifying risk biomarkers.
What parents need to know on December 11, 2025
For future parents, the most important thing is that today the path of care is well-trodden: regular prenatal check-ups, timely diagnostics, early consultation with a craniofacial team, a surgical plan, and continuous support during the child's growth. Science is simultaneously rapidly mapping the fine mechanics of lip and palate fusion. Every new step – from discovering the role of actomyosin forces to defining the threshold of cadherin adhesion and the stabilizing role of p120-catenin – brings us closer to better outcomes and potential, targeted interventions in the future.
How do these insights connect with public health messages? Very simply: cessation of smoking and optimization of nutrition during pregnancy, along with standard folic acid supplementation according to recommendations, remain key decisions that reduce risk. Timely referral to experienced centers allows for the correct sequence of steps, from feeding and hearing to speech. And the support of the community, parent associations, and institutions makes a difference in the daily life of families.
On the horizon, thanks to long-term, stable funding and collaboration between basic and clinical science, a new generation of solutions is appearing – not necessarily spectacular, but very concrete: more precise ultrasound protocols, better outcome metrics, standardized practices with demonstrable benefits, and, perhaps one day, biological "enhancers" of fusion. Until then, we know enough to ensure every child with a cleft has a structured, safe, and humane path through treatment.
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Creation time: 11 December, 2025