RESUMEN
The evolutionary theory of language predicts that a language will tend towards fewer synonyms for a given object. We subject this and related predictions to empirical tests, using data from the eBay Big Data Lab which let us access all records of the words used by eBay vendors in their item titles, and by consumers in their searches. We find support for the predictions of the evolutionary theory of language. In particular, the mapping from object to words sharpens over time on both sides of the market, i.e. among consumers and among vendors. In addition, the word mappings used on the two sides of the market become more similar over time. Our research contributes to the literature on language evolution by reporting results of a truly unique large-scale empirical study.
Asunto(s)
Desarrollo del Lenguaje , Lingüística , Investigación Empírica , HumanosRESUMEN
Hedgehog (Hh) is a core signaling pathway implicated in fundamental processes during embryonic kidney development. We previously found that loss-of-function mutations in the transcription factor GLIS2, a putative vertebrate ortholog of Drosophila Ci, cause nephronophthisis type 7 in humans and mice. Kidney tubular cells in Glis2-knockout mice acquire mesenchymal phenotype, but the cellular mechanisms of this transition are unknown. Here, we demonstrate that Glis2 is a functional component of Hh signaling and is necessary to suppress this pathway in the postnatal kidney. In the epithelial compartment, Glis2 opposes Gli1 activity by binding cis-acting regulatory sequences in the 5' flanking regions of Snai1 and Wnt4, thereby inhibiting de-differentiation of tubular cells. We conclude that Glis2 is necessary to inhibit Hh signaling and to maintain the mature tubular epithelial phenotype in the adult kidney. This is the first description of a molecular mechanism that links the Hh signaling pathway to cystic kidney diseases and can open new avenues for the treatment of diverse ciliopathies.
Asunto(s)
Proteínas Hedgehog/metabolismo , Nefronas/crecimiento & desarrollo , Nefronas/metabolismo , Transducción de Señal , Animales , Animales Recién Nacidos , Diferenciación Celular/genética , Células Cultivadas , Células Epiteliales/metabolismo , Células Epiteliales/patología , Transición Epitelial-Mesenquimal/genética , Regulación del Desarrollo de la Expresión Génica , Células HEK293 , Proteínas Hedgehog/genética , Humanos , Factores de Transcripción de Tipo Kruppel/metabolismo , Ratones , Nefronas/patología , Proteínas del Tejido Nervioso/metabolismo , Factor de Transcripción PAX2/metabolismo , Fenotipo , Unión Proteica , Secuencias Reguladoras de Ácidos Nucleicos/genética , Factores de Transcripción de la Familia Snail , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Proteína Wnt4/genética , Proteína Wnt4/metabolismo , Proteína con Dedos de Zinc GLI1RESUMEN
Nephronophthisis (NPHP) is the most frequent genetic cause of end-stage renal failure in the first three decades of life. It is characterized primarily by renal cysts with extrarenal involvements of the eye and brain. Ten recessive genes responsible for NPHP have been identified by positional cloning. This discovery supported a unifying theory of renal cystic disease, which states that all proteins mutated in cystic kidney diseases of human, mice, or zebrafish are expressed in primary cilia of renal epithelial cells. Mutations in nephrocystin-3 (NPHP3) are the cause of human nephronophthisis type 3 and polycystic kidney disease (pcy) mouse mutants. To study the functional role of NPHP3 in normal embryonic development and in the pathogenesis of cystic kidney disease, we characterized the zebrafish ortholog nphp3 by morpholino oligo (MO)-mediated knockdown. When nphp3 function was suppressed by either of the two MOs blocking the translation of the protein or the splicing of mRNA, zebrafish embryos displayed hydrocephalus and pronephric cysts. Knockdown of nphp3 also led to situs inversus phenotypes due to defective cilia at Kupffer's vesicle. We showed that nphp3 genetically interacts with nphp2/inversin and human NPHP3 localizes to primary cilia in Madin-Darby canine kidney cells. Like nphp2/inversin, nphp3 knockdown affected morphogenic cell movement during gastrulation, suggesting nphp3 is essential to regulate convergent extension. Thus nphp3, cooperating with nphp2/inversin, plays an essential role related to ciliary function, and the knockdown provides an animal model that may be used for studies of the pathogenesis and therapy for this disease.