The Rho GTPase and Fyn tyrosine kinase have been implicated previously in positive control of keratinocyte cell–cell adhesion. Here, we show that Rho and Fyn operate along the same signaling pathway. Endogenous Rho activity increases in differentiating keratinocytes and is required for both Fyn kinase activation and increased tyrosine phosphorylation of β- and γ-catenin, which is associated with the establishment of keratinocyte cell–cell adhesion. Conversely, expression of constitutive active Rho is sufficient to promote cell–cell adhesion through a tyrosine kinase- and Fyn-dependent mechanism, trigger Fyn kinase activation, and induce tyrosine phosphorylation of β- and γ-catenin and p120ctn. The positive effects of activated Rho on cell–cell adhesion are not induced by an activated Rho mutant with defective binding to the serine/threonine PRK2/PKN kinases. Endogenous PRK2 kinase activity increases with keratinocyte differentiation, and, like activated Rho, increased PRK2 activity promotes keratinocyte cell–cell adhesion and induces tyrosine phosphorylation of β- and γ-catenin and Fyn kinase activation. Thus, these findings reveal a novel role of Fyn as a downstream mediator of Rho in control of keratinocyte cell–cell adhesion and implicate the PRK2 kinase, a direct Rho effector, as a link between Rho and Fyn activation.

The development and the function of central nervous system depend on thyroid hormones. In humans, the lack of thyroid hormones causes cretinism, a syndrome of severe mental deficiency. It is assumed that thyroid hormones affect the normal development and function of the brain by activating or suppressing target gene expression because several genes expressed in the brain have been shown to be under thyroid hormone control. Among these, the Rhes gene, encoding a small GTP-binding protein, is predominantly expressed in the striatal region of the brain. To clarify the role of Rhes in vivo, we disrupted the Rhes gene by homologous recombination in embryonic stem cells and generated mice homozygous for the Rhes null mutation (Rhes ؊/؊ ). Rhes ؊/؊ mice were viable but weighed less than wild-type mice. Furthermore, they showed behavioral abnormalities, displaying a gender-dependent increase in anxiety levels and a clear motor coordination deficit but no learning or memory impairment. These results suggest that Rhes disruption affects selected behavioral competencies.The thyroid hormones thyroxine (T 4 ) and triiodothyronine (T 3 ) have many physiological effects. They exert their actions in all tissues examined and affect many metabolic pathways. Some of the most prominent effects of thyroid hormones occur during fetal development and in early childhood. In humans, the lack of adequate levels of thyroid hormones in the first trimester of life, such as in iodine deficiency (endemic cretinism) (8, 9), or in developmental abnormalities of the thyroid gland (congenital hypothyroidism) (22, 28, 55) results in cretinism, a syndrome of severe mental deficiency, which may be accompanied by retarded growth and/or neurological deficits, such as spastic diplegia. Many of these developmental effects are not reversed by later treatment with hormone, indicating that thyroid hormone acts in a specific developmental window. Therefore, adequate levels of thyroid hormone are required for normal central nervous system development.To date, several specific central nervous system genes whose expression is controlled by thyroid hormone have been identified. The expression of these genes may be decreased (2, 5) or increased (1, 18) in hypothyroidism. Furthermore, the total or partial absence of thyroid hormones may also affect either mRNA stability (43, 54) or the mRNA translational process (43,57,60). The identification of thyroid hormone target genes in the central nervous system and the understanding of their function in central nervous system development are important to understanding the pathogenesis of neurological cretinism at the molecular level.In order to understand the molecular basis of neurological cretinism, we studied the Rhes (Ras homolog enriched in striatum) gene (24). Rhes is predominantly expressed in the striatum, and its expression is controlled by thyroid hormones (59). Interestingly, several lines of evidence indicate that in neurological cretinism, there is damage of striatum, which determines a striatopallidal syndr...

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