RESUMO
Multinucleate cellular syncytial formation is a hallmark of skeletal muscle differentiation. Myomaker, encoded by Mymk (Tmem8c), is a well-conserved plasma membrane protein required for myoblast fusion to form multinucleated myotubes in mouse, chick, and zebrafish. Here, we report that autosomal recessive mutations in MYMK (OMIM 615345) cause Carey-Fineman-Ziter syndrome in humans (CFZS; OMIM 254940) by reducing but not eliminating MYMK function. We characterize MYMK-CFZS as a congenital myopathy with marked facial weakness and additional clinical and pathologic features that distinguish it from other congenital neuromuscular syndromes. We show that a heterologous cell fusion assay in vitro and allelic complementation experiments in mymk knockdown and mymkinsT/insT zebrafish in vivo can differentiate between MYMK wild type, hypomorphic and null alleles. Collectively, these data establish that MYMK activity is necessary for normal muscle development and maintenance in humans, and expand the spectrum of congenital myopathies to include cell-cell fusion deficits.
Assuntos
Proteínas de Membrana/genética , Síndrome de Möbius/genética , Morfogênese/genética , Proteínas Musculares/genética , Músculo Esquelético/metabolismo , Doenças Musculares/genética , Mutação , Mioblastos/metabolismo , Síndrome de Pierre Robin/genética , Proteínas de Peixe-Zebra/genética , Adulto , Sequência de Aminoácidos , Animais , Fusão Celular , Criança , Modelos Animais de Doenças , Embrião não Mamífero , Feminino , Expressão Gênica , Genes Recessivos , Teste de Complementação Genética , Humanos , Lactente , Masculino , Proteínas de Membrana/deficiência , Síndrome de Möbius/metabolismo , Síndrome de Möbius/patologia , Proteínas Musculares/deficiência , Músculo Esquelético/crescimento & desenvolvimento , Músculo Esquelético/patologia , Doenças Musculares/metabolismo , Doenças Musculares/patologia , Mioblastos/patologia , Linhagem , Síndrome de Pierre Robin/metabolismo , Síndrome de Pierre Robin/patologia , Alinhamento de Sequência , Homologia de Sequência de Aminoácidos , Peixe-Zebra , Proteínas de Peixe-Zebra/deficiênciaRESUMO
Although a number of repair strategies have been shown to promote axon outgrowth following neuronal injury in the mammalian CNS, it remains unclear whether regenerated axons establish functional synapses and support behavior. Here, in both juvenile and adult mice, we show that either PTEN and SOCS3 co-deletion, or co-overexpression of osteopontin (OPN)/insulin-like growth factor 1 (IGF1)/ciliary neurotrophic factor (CNTF), induces regrowth of retinal axons and formation of functional synapses in the superior colliculus (SC) but not significant recovery of visual function. Further analyses suggest that regenerated axons fail to conduct action potentials from the eye to the SC due to lack of myelination. Consistent with this idea, administration of voltage-gated potassium channel blockers restores conduction and results in increased visual acuity. Thus, enhancing both regeneration and conduction effectively improves function after retinal axon injury.
Assuntos
Axônios/fisiologia , Colículos Superiores/fisiologia , 4-Aminopiridina/farmacologia , Animais , Axônios/efeitos dos fármacos , Fator Neurotrófico Ciliar/metabolismo , Fenômenos Eletrofisiológicos , Olho/metabolismo , Fator de Crescimento Insulin-Like I/metabolismo , Camundongos , Bainha de Mielina/metabolismo , Nervo Óptico , Osteopontina/metabolismo , PTEN Fosfo-Hidrolase/metabolismo , Bloqueadores dos Canais de Potássio/farmacologia , Regeneração/efeitos dos fármacos , Proteína 3 Supressora da Sinalização de Citocinas , Proteínas Supressoras da Sinalização de Citocina/metabolismo , SinapsesRESUMO
BACKGROUND: Mutations in three functionally diverse genes cause Rett Syndrome. Although the functions of Forkhead box G1 (FOXG1), Methyl CpG binding protein 2 (MECP2) and Cyclin-dependent kinase-like 5 (CDKL5) have been studied individually, not much is known about their relation to each other with respect to expression levels and regulatory regions. Here we analyzed data from hundreds of mouse and human samples included in the FANTOM5 project, to identify transcript initiation sites, expression levels, expression correlations and regulatory regions of the three genes. RESULTS: Our investigations reveal the predominantly used transcription start sites (TSSs) for each gene including novel transcription start sites for FOXG1. We show that FOXG1 expression is poorly correlated with the expression of MECP2 and CDKL5. We identify promoter shapes for each TSS, the predicted location of enhancers for each gene and the common transcription factors likely to regulate the three genes. Our data imply Polycomb Repressive Complex 2 (PRC2) mediated silencing of Foxg1 in cerebellum. CONCLUSIONS: Our analyses provide a comprehensive picture of the regulatory regions of the three genes involved in Rett Syndrome.
Assuntos
Perfilação da Expressão Gênica , Regiões Promotoras Genéticas/genética , Síndrome de Rett/genética , Animais , Encéfalo/metabolismo , Encéfalo/patologia , Linhagem Celular Tumoral , Ilhas de CpG/genética , Fatores de Transcrição Forkhead/genética , Genômica , Histonas/genética , Humanos , Proteína 2 de Ligação a Metil-CpG/genética , Camundongos , Proteínas do Tecido Nervoso/genética , Neurônios/metabolismo , Proteínas Serina-Treonina Quinases/genética , Síndrome de Rett/patologia , TATA Box/genética , Sítio de Iniciação de TranscriçãoRESUMO
The mature optic nerve cannot regenerate when injured, leaving victims of traumatic nerve damage or diseases such as glaucoma with irreversible visual losses. Recent studies have identified ways to stimulate retinal ganglion cells to regenerate axons part-way through the optic nerve, but it remains unknown whether mature axons can reenter the brain, navigate to appropriate target areas, or restore vision. We show here that with adequate stimulation, retinal ganglion cells are able to regenerate axons the full length of the visual pathway and on into the lateral geniculate nucleus, superior colliculus, and other visual centers. Regeneration partially restores the optomotor response, depth perception, and circadian photoentrainment, demonstrating the feasibility of reconstructing central circuitry for vision after optic nerve damage in mature mammals.