RESUMEN
Multipotent progenitors in the vertebrate retina often generate clonally related mixtures of excitatory and inhibitory neurons. The postmitotically expressed transcription factor, Ptf1a, is essential for all inhibitory fates in the zebrafish retina, including three types of horizontal and 28 types of amacrine cell. Here, we show that specific types of inhibitory neurons arise from the cell-autonomous influence of Ptf1a in the daughters of fate-restricted progenitors, such as Ath5 or Vsx1/2-expressing progenitors, and that in the absence of Ptf1a, cells that would have become these specific inhibitory subtypes revert to the histogenetically appropriate excitatory subtypes of the same lineage. Altered proportions of amacrine subtypes respecified by the misexpression of Ptf1a in the Ath5 lineage suggest that Ath5-expressing progenitors are biased, favoring the generation of some subtypes more than others. Yet the full array of inhibitory cell subtypes in Ath5 mutants implies the existence of Ath5-independent factors involved in inhibitory cell specification. We also show that an extrinsic negative feedback on the expression of Ptf1a provides a control mechanism by which the number of any and all types of inhibitory cells in the retina can be regulated in this lineage-dependent way.
Asunto(s)
Diferenciación Celular/genética , Linaje de la Célula/genética , Regulación del Desarrollo de la Expresión Génica/fisiología , Inhibición Neural/fisiología , Retina/citología , Células Amacrinas/clasificación , Células Amacrinas/fisiología , Animales , Animales Modificados Genéticamente , Blastómeros/trasplante , Bromodesoxiuridina/metabolismo , Diferenciación Celular/efectos de los fármacos , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Embrión no Mamífero , Células Madre Embrionarias/efectos de los fármacos , Células Madre Embrionarias/fisiología , Regulación del Desarrollo de la Expresión Génica/genética , Glicina/metabolismo , Proteínas Fluorescentes Verdes/genética , Proteínas Luminiscentes/genética , Proteínas del Tejido Nervioso/genética , Proteínas del Tejido Nervioso/metabolismo , Inhibición Neural/genética , Oligonucleótidos Antisentido/farmacología , Retina/metabolismo , Trasplante de Células Madre/métodos , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Pez Cebra , Proteínas de Pez Cebra/genética , Proteínas de Pez Cebra/metabolismo , Ácido gamma-Aminobutírico/metabolismo , Proteína Fluorescente RojaRESUMEN
INTRODUCTION: The goal of this study was to add a predictive modeling approach to the meta-analysis of continuing medical education curricula to determine whether this technique can be used to better understand clinical decision making. Using the education of rheumatologists on rheumatoid arthritis management as a model, this study demonstrates how the combined methodology has the ability to not only characterize learning gaps but also identify those proficiency areas that have the greatest impact on clinical behavior. METHODS: The meta-analysis included seven curricula with 25 activities. Learners who identified as rheumatologists were evaluated across multiple learning domains, using a uniform methodology to characterize learning gains and gaps. A performance composite variable (called the treatment individualization and optimization score) was then established as a target upon which predictive analytics were conducted. RESULTS: Significant predictors of the target included items related to the knowledge of rheumatologists and confidence concerning 1) treatment guidelines and 2) tests that measure disease activity. In addition, a striking demographic predictor related to geographic practice setting was also identified. DISCUSSION: The results demonstrate the power of advanced analytics to identify key predictors that influence clinical behaviors. Furthermore, the ability to provide an expected magnitude of change if these predictors are addressed has the potential to substantially refine educational priorities to those drivers that, if targeted, will most effectively overcome clinical barriers and lead to the greatest success in achieving treatment goals.