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1.
MicroPubl Biol ; 20222022.
Artigo em Inglês | MEDLINE | ID: mdl-36530475

RESUMO

Germline stem cell proliferation in C. elegans requires activation of the GLP-1/Notch receptor, which is located on the germline plasma membrane and encoded by the glp-1 gene. We previously identified several genes whose products directly or indirectly promote activity of the GLP-1 signaling pathway by finding mutations that enhance the germline phenotype of a glp-1(ts) allele, glp-1(bn18) . Here, we report phenotypic and molecular analysis of a new ekl-1 allele, ekl-1(om92) , that enhances the glp-1(bn18) phenotype. ekl-1(om92) is a 244 bp deletion predicted to generate a frameshift and premature termination codon, yielding a severely truncated protein, suggesting it is a null allele.

3.
FASEB J ; 33(8): 8745-8758, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31002540

RESUMO

A single pool of multipotent retinal progenitor cells give rise to the diverse cell types within the mammalian retina. Such cellular diversity is due to precise control of various cellular processes like cell specification, proliferation, differentiation, and maturation. Circadian clock genes can control the expression of key regulators of cell cycle progression and therefore can synchronize the cell cycle state of a heterogeneous population of cells. Here we show that the protein encoded by the circadian clock gene brain and muscle arnt-like protein-1 (Bmal1) is expressed in the embryonic retina and is required to regulate the timing of cell cycle exit. Accordingly, loss of Bmal1 during retinal neurogenesis results in increased S-phase entry and delayed cell cycle exit. Disruption in cell cycle kinetics affects the timely generation of the appropriate neuronal population thus leading to an overall decrease in the number of retinal ganglion cells, amacrine cells, and an increase in the number of the late-born type II cone bipolar cells as well as the Müller glia. Additionally, the mislocalized Müller cells are observed in the photoreceptor layer in the Bmal1 conditional mutants. These changes affect the functional integrity of the visual circuitry as we report a significant delay in visual evoked potential implicit time in the retina-specific Bmal1 null animals. Our results demonstrate that Bmal1 is required to maintain the balance between the neural and glial cells in the embryonic retina by coordinating the timing of cell cycle entry and exit. Thus, Bmal1 plays an essential role during retinal neurogenesis affecting both development and function of the mature retina.-Sawant, O. B., Jidigam, V. K., Fuller, R. D., Zucaro, O. F., Kpegba, C., Yu, M., Peachey, N. S., Rao, S. The circadian clock gene Bmal1 is required to control the timing of retinal neurogenesis and lamination of Müller glia in the mouse retina.


Assuntos
Fatores de Transcrição ARNTL/metabolismo , Células Ependimogliais/metabolismo , Neurogênese , Retina/citologia , Fatores de Transcrição ARNTL/genética , Células Amácrinas/citologia , Células Amácrinas/metabolismo , Animais , Ciclo Celular , Relógios Circadianos , Células Ependimogliais/citologia , Potenciais Evocados Visuais , Camundongos , Retina/embriologia , Retina/metabolismo , Retina/fisiologia , Células Ganglionares da Retina/citologia , Células Ganglionares da Retina/metabolismo
4.
Cell Rep ; 21(3): 692-706, 2017 Oct 17.
Artigo em Inglês | MEDLINE | ID: mdl-29045837

RESUMO

Circadian clocks regulate various aspects of photoreceptor physiology, but their contribution to photoreceptor development and function is unclear. Cone photoreceptors are critical for color vision. Here, we define the molecular function of circadian activity within cone photoreceptors and reveal a role for the clock genes Bmal1 and Per2 in regulating cone spectral identity. ChIP analysis revealed that BMAL1 binds to the promoter region of the thyroid hormone (TH)-activating enzyme type 2 iodothyronine deiodinase (Dio2) and thus regulates the expression of Dio2. TH treatment resulted in a partial rescue of the phenotype caused by the loss of Bmal1, thus revealing a functional relationship between Bmal1 and Dio2 in establishing cone photoreceptor identity. Furthermore, Bmal1 and Dio2 are required to maintain cone photoreceptor functional integrity. Overall, our results suggest a mechanism by which circadian proteins can locally regulate the availability of TH and influence tissue development and function.


Assuntos
Fatores de Transcrição ARNTL/genética , Relógios Circadianos/genética , Células Fotorreceptoras Retinianas Cones/metabolismo , Hormônios Tireóideos/metabolismo , Fatores de Transcrição ARNTL/metabolismo , Envelhecimento , Sequência de Aminoácidos , Animais , Relógios Circadianos/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Iodeto Peroxidase/química , Iodeto Peroxidase/genética , Iodeto Peroxidase/metabolismo , Camundongos Knockout , Opsinas/metabolismo , Proteínas Circadianas Period/metabolismo , Células Fotorreceptoras Retinianas Cones/efeitos dos fármacos , Tri-Iodotironina/farmacologia , Iodotironina Desiodinase Tipo II
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