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1.
PLoS One ; 18(5): e0284824, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37141220

RESUMEN

Neurons in the hypothalamic preoptic area (POA) regulate multiple homeostatic processes, including thermoregulation and sleep, by sensing afferent input and modulating sympathetic nervous system output. The POA has an autonomous circadian clock and may also receive circadian signals indirectly from the suprachiasmatic nucleus. We have previously defined a subset of neurons in the POA termed QPLOT neurons that are identified by the expression of molecular markers (Qrfp, Ptger3, LepR, Opn5, Tacr3) that suggest receptivity to multiple stimuli. Because Ptger3, Opn5, and Tacr3 encode G-protein coupled receptors (GPCRs), we hypothesized that elucidating the G-protein signaling in these neurons is essential to understanding the interplay of inputs in the regulation of metabolism. Here, we describe how the stimulatory Gs-alpha subunit (Gnas) in QPLOT neurons regulates metabolism in mice. We analyzed Opn5cre; Gnasfl/fl mice using indirect calorimetry at ambient temperatures of 22°C (a historical standard), 10°C (a cold challenge), and 28°C (thermoneutrality) to assess the ability of QPLOT neurons to regulate metabolism. We observed a marked decrease in nocturnal locomotion of Opn5cre; Gnasfl/fl mice at both 28°C and 22°C, but no overall differences in energy expenditure, respiratory exchange, or food and water consumption. To analyze daily rhythmic patterns of metabolism, we assessed circadian parameters including amplitude, phase, and MESOR. Loss-of-function GNAS in QPLOT neurons resulted in several subtle rhythmic changes in multiple metabolic parameters. We observed that Opn5cre; Gnasfl/fl mice show a higher rhythm-adjusted mean energy expenditure at 22°C and 10°C, and an exaggerated respiratory exchange shift with temperature. At 28°C, Opn5cre; Gnasfl/fl mice have a significant delay in the phase of energy expenditure and respiratory exchange. Rhythmic analysis also showed limited increases in rhythm-adjusted means of food and water intake at 22°C and 28°C. Together, these data advance our understanding of Gαs-signaling in preoptic QPLOT neurons in regulating daily patterns of metabolism.


Asunto(s)
Regulación de la Temperatura Corporal , Hipotálamo , Animales , Ratones , Regulación de la Temperatura Corporal/fisiología , Ritmo Circadiano/fisiología , Metabolismo Energético , Homeostasis , Hipotálamo/metabolismo , Proteínas de la Membrana/metabolismo , Neuronas/metabolismo , Opsinas/metabolismo , Temperatura
2.
Cell Res ; 33(2): 89-90, 2023 02.
Artículo en Inglés | MEDLINE | ID: mdl-36195752
3.
Immunity ; 55(12): 2318-2335.e7, 2022 12 13.
Artículo en Inglés | MEDLINE | ID: mdl-36379210

RESUMEN

Microglia utilize their phagocytic activity to prune redundant synapses and refine neural circuits during precise developmental periods. However, the neuronal signals that control this phagocytic clockwork remain largely undefined. Here, we show that neuronal signal-regulatory protein alpha (SIRPα) is a permissive cue for microglial phagocytosis in the developing murine retina. Removal of neuronal, but not microglial, SIRPα reduced microglial phagocytosis, increased synpase numbers, and impaired circuit function. Conversely, prolonging neuronal SIRPα expression extended developmental microglial phagocytosis. These outcomes depended on the interaction of presynaptic SIRPα with postsynaptic CD47. Global CD47 deficiency modestly increased microglial phagocytosis, while CD47 overexpression reduced it. This effect was rescued by coexpression of neuronal SIRPα or codeletion of neuronal SIRPα and CD47. These data indicate that neuronal SIRPα regulates microglial phagocytosis by limiting microglial SIRPα access to neuronal CD47. This discovery may aid our understanding of synapse loss in neurological diseases.


Asunto(s)
Antígeno CD47 , Receptores Inmunológicos , Ratones , Animales , Antígeno CD47/metabolismo , Receptores Inmunológicos/metabolismo , Macrófagos/metabolismo , Fagocitosis/fisiología , Retina , Antígenos de Diferenciación/metabolismo
4.
Dev Biol ; 476: 218-239, 2021 08.
Artículo en Inglés | MEDLINE | ID: mdl-33848537

RESUMEN

Synapses in the outer retina are the first information relay points in vision. Here, photoreceptors form synapses onto two types of interneurons, bipolar cells and horizontal cells. Because outer retina synapses are particularly large and highly ordered, they have been a useful system for the discovery of mechanisms underlying synapse specificity and maintenance. Understanding these processes is critical to efforts aimed at restoring visual function through repairing or replacing neurons and promoting their connectivity. We review outer retina neuron synapse architecture, neural migration modes, and the cellular and molecular pathways that play key roles in the development and maintenance of these connections. We further discuss how these mechanisms may impact connectivity in the retina.


Asunto(s)
Células Fotorreceptoras/citología , Sinapsis/metabolismo , Visión Ocular/fisiología , Animales , Humanos , Interneuronas/fisiología , Células Fotorreceptoras/fisiología , Retina/fisiología , Células Fotorreceptoras Retinianas Conos/fisiología , Células Horizontales de la Retina/fisiología , Sinapsis/fisiología
5.
Cell Rep ; 34(5): 108698, 2021 02 02.
Artículo en Inglés | MEDLINE | ID: mdl-33535040

RESUMEN

Cone photoreceptors detect light and are responsible for color vision. These cells display a distinct polarized morphology where nuclei are precisely aligned in the apical retina. However, little is known about the mechanisms involved in cone nuclear positioning or the impact of this organization on retina function. We show that the serine/threonine kinase LKB1 and one of its substrates, AMPK, regulate cone nuclear positioning. In the absence of either molecule, cone nuclei are misplaced along the axon, resulting in altered nuclear lamination. LKB1 is required specifically in cones to mediate this process, and disruptions in nuclear alignment result in reduced cone function. Together, these results identify molecular determinants of cone nuclear position and indicate that cone nuclear position alignment enables proper visual function.


Asunto(s)
Proteínas Quinasas Activadas por AMP/metabolismo , Visión Ocular/fisiología , Animales , Ratones
6.
Front Neural Circuits ; 14: 583391, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-33177995

RESUMEN

During development, neurons generate excess processes which are then eliminated in concert with circuit maturation. C1q is the initiating protein in the complement cascade and has been implicated in this process, but whether C1q-mediated elimination is targeted to particular neural compartments is unclear. Using the murine retina, we identify C1q as a specific regulator of horizontal cell neurite confinement. Subsets of horizontal cell dendritic and axonal neurites extend into the outer retina suggesting that complement achieves both cellular and subcellular selectivity. These alterations emerge as outer retina synapses become mature. C1q expression is restricted to retina microglia, and the loss of C1q results in decreased microglia activation. This pathway appears independent of the C3a receptor (C3aR) and complement receptor 3 (CR3), as horizontal cells are normal when either protein is absent. Together, these data identify a new role for C1q in cell and neurite-specific confinement and implicate microglia-mediated phagocytosis in this process.


Asunto(s)
Complemento C1q/fisiología , Microglía/metabolismo , Neuritas/fisiología , Plasticidad Neuronal/fisiología , Animales , Complemento C3a , Ratones , Ratones Noqueados , Microglía/fisiología , Fagocitosis , Receptores de Complemento , Células Horizontales de la Retina
7.
Elife ; 92020 05 07.
Artículo en Inglés | MEDLINE | ID: mdl-32378514

RESUMEN

Structural changes in pre and postsynaptic neurons that accompany synapse formation often temporally and spatially overlap. Thus, it has been difficult to resolve which processes drive patterned connectivity. To overcome this, we use the laminated outer murine retina. We identify the serine/threonine kinase LKB1 as a key driver of synapse layer emergence. The absence of LKB1 in the retina caused a marked mislocalization and delay in synapse layer formation. In parallel, LKB1 modulated postsynaptic horizontal cell refinement and presynaptic photoreceptor axon growth. Mislocalized horizontal cell processes contacted aberrant cone axons in LKB1 mutants. These defects coincided with altered synapse protein organization, and horizontal cell neurites were misdirected to ectopic synapse protein regions. Together, these data suggest that LKB1 instructs the timing and location of connectivity in the outer retina via coordinate regulation of pre and postsynaptic neuron structure and the localization of synapse-associated proteins.


Asunto(s)
Neuritas/enzimología , Neurogénesis , Células Fotorreceptoras/enzimología , Proteínas Serina-Treonina Quinasas/metabolismo , Sinapsis/enzimología , Proteínas Quinasas Activadas por AMP , Animales , Femenino , Masculino , Ratones Noqueados , Mutación , Proteínas Serina-Treonina Quinasas/genética , Transporte de Proteínas , Proteína 1 de Transporte Vesicular de Glutamato/metabolismo
8.
J Comp Neurol ; 528(5): 729-755, 2020 04 01.
Artículo en Inglés | MEDLINE | ID: mdl-31609468

RESUMEN

In several areas of the central nervous system, neurons are regionally organized into groups or layers that carry out specific activities. In this form of patterning, neurons of distinct types localize their cell bodies to just one or a few of the layers within a structure. However, little is known about whether diverse neuron types within a lamina share molecular features that coordinate their organization. To begin to identify such candidates, we used the laminated murine retina to screen 92 lacZ reporter lines available through the Knockout Mouse Project. Thirty-two of these displayed reporter expression in restricted subsets of inner retina neurons. We then identified the spatiotemporal expression patterns of these genes at key developmental stages. This uncovered several that were heavily enriched in development but reduced in adulthood, including the transcriptional regulator Hmga1. An additional set of genes displayed maturation associated laminar enrichment. Among these, we identified Bbox1 as a novel gene that specifically labels all neurons in the ganglion cell layer but is largely excluded from otherwise molecularly similar neurons in the inner retina. Finally, we established Dbn1 as a new marker enriched in amacrines and Fmnl3 as a marker for subsets of αRGCs. Together, these data provide a spatiotemporal map for laminae-specific molecules and suggest that diverse neuron types within a lamina share coordinating molecular features that may inform their fate or function.


Asunto(s)
Neuronas Retinianas/citología , Animales , Ratones
9.
Neurochem Int ; 129: 104486, 2019 10.
Artículo en Inglés | MEDLINE | ID: mdl-31175897

RESUMEN

Neuron function relies on and instructs the development and precise organization of neurovascular units that in turn support circuit activity. However, our understanding of the molecular cues that regulate this relationship remains sparse. Using a high-throughput screening pipeline, we recently identified several new regulators of vascular patterning. Among these was the potassium channel tetramerization domain-containing protein 7 (KCTD7). Mutations in KCTD7 are associated with progressive myoclonic epilepsy, but how KCTD7 regulates neural development and function remains poorly understood. To begin to identify such mechanisms, we focus on mouse retina, a tractable part of the central nervous system that contains precisely ordered neuron subtypes supported by a trilaminar vascular network. We find that deletion of Kctd7 induces defective patterning of the adult retina vascular network, resulting in increased branching, vessel length, and lacunarity. These alterations reflect early and specific defects in vessel development, as emergence of the superficial and deep vascular layers were delayed. These defects are likely due to a role for Kctd7 in inner retina neurons. Kctd7 is absent from vessels but present in neurons in the inner retina, and its deletion resulted in a corresponding increase in the number of bipolar cells in development and increased vessel branching in adults. These alterations were accompanied by retinal function deficits. Together, these data suggest that neuronal Kctd7 drives growth and patterning of the vasculature and that neurovascular interactions may participate in the pathogenesis of KCTD7-related human diseases.


Asunto(s)
Canales de Potasio/fisiología , Vasos Retinianos/fisiología , Animales , Electrorretinografía , Femenino , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Epilepsias Mioclónicas Progresivas/genética , Canales de Potasio/deficiencia , Canales de Potasio/genética , ARN Mensajero/biosíntesis , Retina/ultraestructura , Células Bipolares de la Retina/patología , Vasos Retinianos/crecimiento & desarrollo , Vasos Retinianos/patología
10.
Cell Rep ; 24(9): 2506-2519, 2018 08 28.
Artículo en Inglés | MEDLINE | ID: mdl-30157441

RESUMEN

Retinal function relies on precisely organized neurons and synapses and a properly patterned vasculature to support them. Alterations in these features can result in vision loss. However, our understanding of retinal organization pathways remains incomplete because of a lack of methods to rapidly identify neuron and vasculature regulators in mammals. Here we developed a pipeline for the identification of neural and synaptic integrity genes by high-throughput retinal screening (INSiGHT) that analyzes candidate expression, vascular patterning, cellular organization, and synaptic arrangement. Using this system, we examined 102 mutant mouse lines and identified 16 unique retinal regulatory genes. Fifteen of these candidates are identified as novel retina regulators, and many (9 of 16) are associated with human neural diseases. These results expand the genetic landscape involved in retinal circuit organization and provide a road map for continued discovery of mammalian retinal regulators and disease-causing alleles.


Asunto(s)
Neuronas/fisiología , Retina/fisiología , Humanos , Sinapsis
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