RESUMEN
Cleft palate is a common congenital disorder that affects up to 1 in 2500 live births and results in considerable morbidity to affected individuals and their families. The aetiology of cleft palate is complex with both genetic and environmental factors implicated. Mutations in the transcription factor p63 are one of the major individual causes of cleft palate; however, the gene regulatory networks in which p63 functions remain only partially characterized. Our findings demonstrate that p63 functions as an essential regulatory molecule in the spatio-temporal control of palatal epithelial cell fate to ensure appropriate fusion of the palatal shelves. Initially, p63 induces periderm formation and controls its subsequent maintenance to prevent premature adhesion between adhesion-competent, intra-oral epithelia. Subsequently, TGFß3-induced down-regulation of p63 in the medial edge epithelia of the palatal shelves is a pre-requisite for palatal fusion by facilitating periderm migration from, and reducing the proliferative potential of, the midline epithelial seam thereby preventing cleft palate.
Asunto(s)
Fisura del Paladar/genética , Redes Reguladoras de Genes/genética , Fosfoproteínas/genética , Transactivadores/genética , Factor de Crecimiento Transformador beta3/genética , Animales , Movimiento Celular/genética , Proliferación Celular/genética , Fisura del Paladar/fisiopatología , Modelos Animales de Enfermedad , Células Epiteliales/metabolismo , Regulación del Desarrollo de la Expresión Génica , Humanos , Ratones , Mutación , Fosfoproteínas/biosíntesis , Transducción de Señal/genética , Transactivadores/biosíntesisRESUMEN
Understanding human cognitive ageing is important to improve the health of an increasing elderly population. Serum uric acid levels have been linked to many ageing illnesses and are also linked to cognitive functioning, though the direction of the association is equivocal. SLC2A9, a urate transporter, influences uric acid levels. This study first tested four SLC2A9 SNPs, previously associated with uric acid levels, in approximately 1000 Scots: the Lothian Birth Cohort 1936 (LBC1936). These participants were tested on general cognitive ability at ages 11 and 70. At age 70, they took a battery of diverse cognitive tests. Two replication cohorts were investigated. First, the LBC1921, who were tested on general cognitive ability at age 11. At ages 79 (n = 520), 83 (n = 281) and age 87 (n = 177), they completed cognitive ability test batteries. Second, the Edinburgh Type 2 Diabetes Study (ET2DS) were tested for cognitive abilities aged between 60 and 75 years (n = 1066). All analyses were adjusted for age, gender, body mass index and either childhood cognitive ability test score (LBC) or vocabulary-a measure of prior cognitive ability in ET2DS. Significant associations were detected with SLC2A9 and a general memory factor in LBC1936 and other individual cognitive ability tests (lowest P = 0.0002). The association with logical memory replicated in LBC1921 at all ages (all P < 0.05). These associations were not replicated in ET2DS (all P > 0.1). If the positive associations withstand, then this study could suggest that higher uric acid levels may be associated with increased performance on memory-related tasks.