RESUMO
Mutations in Patched (PTCH), encoding the Hedgehog (Hh) receptor, underlie Basal Cell Naevus syndrome (BCNS) and, in addition to tumor predisposition, are associated with a wide range of 'patterning' defects. The basis for the underlying patterning problems in Hh-dependent tissues in BCNS and their long-term consequences on tissue homeostasis are, however, not known. Hh signaling is required for normal growth and organization of the mammalian retina and we show that PtchlacZ+/- mice exhibit vitreoretinal abnormalities resembling those found in BCNS patients. The retinas of PtchlacZ+/- mice exhibit abnormal cell cycle regulation, which culminates in photoreceptor dysplasia and Müller cell-derived gliosis. In BCNS, the intraretinal glial response results in epiretinal membrane (ERM) formation, a proliferative and contractile response on the retinal surface. ERMs are a cause of significant visual loss in the general, especially elderly, population. We hypothesize that alteration of Müller cell Hh signaling may play a role in the pathogenesis of such age-related 'idiopathic' ERMs.
Assuntos
Proteínas de Membrana/genética , Retina/anormalidades , Transdução de Sinais , Transativadores/metabolismo , Animais , Síndrome do Nevo Basocelular/genética , Síndrome do Nevo Basocelular/metabolismo , Síndrome do Nevo Basocelular/patologia , Regulação da Expressão Gênica , Proteínas Hedgehog , Humanos , Peptídeos e Proteínas de Sinalização Intracelular , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Transgênicos , Mutação , Receptores Patched , Receptor Patched-1 , Receptores de Superfície Celular , Retina/crescimento & desenvolvimento , Retina/ultraestrutura , Displasia Retiniana/genética , Displasia Retiniana/patologia , Transativadores/genéticaRESUMO
The adult retina is organized into three cellular layers--an outer photoreceptor, a middle interneuron and an inner retinal ganglion cell (RGC) layer. Although the retinal pigment epithelium (RPE) and Müller cells are important in the establishment and maintenance of this organization, the signals involved are unknown. Here we show that Sonic hedgehog signaling from RGCs is required for the normal laminar organization in the vertebrate retina.
Assuntos
Padronização Corporal/genética , Comunicação Celular/genética , Diferenciação Celular/genética , Retina/anormalidades , Células Ganglionares da Retina/metabolismo , Transdução de Sinais/genética , Transativadores/deficiência , Animais , Padronização Corporal/efeitos dos fármacos , Comunicação Celular/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Divisão Celular/efeitos dos fármacos , Divisão Celular/genética , Feminino , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Regulação da Expressão Gênica no Desenvolvimento/fisiologia , Substâncias de Crescimento/farmacologia , Proteínas Hedgehog , Masculino , Camundongos , Camundongos Knockout , Neuroglia/citologia , Neuroglia/efeitos dos fármacos , Neuroglia/metabolismo , Fenótipo , Proteínas Recombinantes de Fusão/farmacologia , Retina/citologia , Retina/metabolismo , Células Ganglionares da Retina/citologia , Células Ganglionares da Retina/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Células-Tronco/citologia , Células-Tronco/metabolismo , Transativadores/genética , Transativadores/farmacologiaRESUMO
The regulatory elements of the murine Thy1.2 gene were used to drive Cre recombinase expression in the nervous system (NS) of transgenic mice. Eleven Thy1-Cre lines exhibited transgene expression in several regions of the central and peripheral nervous systems, including the cerebral cortex, cerebellum, spinal cord, retina, and dorsal root ganglion. Thy1-Cre expression also resulted in region-specific activation of Cre reporter transgenes. Although Thy-1 expression is normally initiated in postmitotic neurons in the perinatal period, we show that the Thy-1.2 expression cassette drives Cre expression in immature proliferative zones in the NS as early as embryonic day 11 and in non-neural tissue. The Thy1.2 transgene cassette, therefore, does not impart transgene expression that is restricted to the NS or to postmitotic neurons within the NS. This panel of Thy1-Cre transgenic mice, however, will be useful reagents for the ablation of genes whose transcripts are spatially or temporally restricted in the developing NS.
