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1.
Dev Cell ; 58(20): 2080-2096.e7, 2023 10 23.
Artigo em Inglês | MEDLINE | ID: mdl-37557174

RESUMO

During nervous system development, neurons choose synaptic partners with remarkable specificity; however, the cell-cell recognition mechanisms governing rejection of inappropriate partners remain enigmatic. Here, we show that mouse retinal neurons avoid inappropriate partners by using the FLRT2-uncoordinated-5 (UNC5) receptor-ligand system. Within the inner plexiform layer (IPL), FLRT2 is expressed by direction-selective (DS) circuit neurons, whereas UNC5C/D are expressed by non-DS neurons projecting to adjacent IPL sublayers. In vivo gain- and loss-of-function experiments demonstrate that FLRT2-UNC5 binding eliminates growing DS dendrites that have strayed from the DS circuit IPL sublayers. Abrogation of FLRT2-UNC5 binding allows mistargeted arbors to persist, elaborate, and acquire synapses from inappropriate partners. Conversely, UNC5C misexpression within DS circuit sublayers inhibits dendrite growth and drives arbors into adjacent sublayers. Mechanistically, UNC5s promote dendrite elimination by interfering with FLRT2-mediated adhesion. Based on their broad expression, FLRT-UNC5 recognition is poised to exert widespread effects upon synaptic partner choices across the nervous system.


Assuntos
Neurônios , Retina , Animais , Camundongos , Neurônios/fisiologia , Transdução de Sinais , Comunicação Celular , Sinapses/fisiologia , Dendritos/fisiologia , Glicoproteínas de Membrana/metabolismo
2.
Dev Biol ; 478: 144-154, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34260962

RESUMO

Throughout the central nervous system, astrocytes adopt precisely ordered spatial arrangements of their somata and arbors, which facilitate their many important functions. Astrocyte pattern formation is particularly important in the retina, where astrocytes serve as a template that dictates the pattern of developing retinal vasculature. Thus, if astrocyte patterning is disturbed, there are severe consequences for retinal angiogenesis and ultimately for vision - as seen in diseases such as retinopathy of prematurity. Here we discuss key steps in development of the retinal astrocyte population. We describe how fundamental developmental forces - their birth, migration, proliferation, and death - sculpt astrocytes into a template that guides angiogenesis. We further address the radical changes in the cellular and molecular composition of the astrocyte network that occur upon completion of angiogenesis, paving the way for their adult functions in support of retinal ganglion cell axons. Understanding development of retinal astrocytes may elucidate pattern formation mechanisms that are deployed broadly by other axon-associated astrocyte populations.


Assuntos
Astrócitos/fisiologia , Retina/crescimento & desenvolvimento , Retina/fisiologia , Animais , Axônios/fisiologia , Morte Celular , Diferenciação Celular , Movimento Celular , Proliferação de Células , Humanos , Neovascularização Fisiológica , Fibras Nervosas/fisiologia , Retina/citologia , Retina/embriologia , Células Ganglionares da Retina/fisiologia , Vasos Retinianos/embriologia , Vasos Retinianos/crescimento & desenvolvimento , Vasos Retinianos/fisiologia , Retinopatia da Prematuridade/patologia , Retinopatia da Prematuridade/fisiopatologia
3.
Glia ; 68(7): 1513-1530, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32065429

RESUMO

The generation of fully functional oligodendrocytes, the myelinating cells of the central nervous system, is preceded by a complex maturational process. We previously showed that the timing of oligodendrocyte differentiation and rat brain myelination were altered by perinatal exposure to buprenorphine and methadone, opioid analogs used for the management of pregnant addicts. Those observations suggested the involvement of the µ-opioid receptor (MOR) and the nociceptin/orphanin FQ receptor (NOR). However, it remained to be determined if these receptors and their endogenous ligands could indeed control the timing of myelination under normal physiological conditions of brain development. We now found that the endogenous MOR ligand endomorphin-1 (EM-1) exerts a striking stimulatory action on cellular and morphological maturation of rat pre-oligodendrocytes, but unexpectedly, these effects appear to be restricted to the cells from the female pups. Critically, this stimulation is abolished by coincubation with the endogenous NOR ligand nociceptin. Furthermore, NOR antagonist treatment of 9-day-old female pups results in accelerated brain myelination. Interestingly, the lack of sex-dependent differences in developmental brain levels of EM-1 and nociceptin, or oligodendroglial expression of MOR and NOR, suggests that the observed sex-specific responses may be highly dependent on important intrinsic differences between the male and female oligodendrocytes. The discovery of a significant effect of EM-1 and nociceptin in the developing female oligodendrocytes and brain myelination, underscores the need for further studies investigating brain sex-related differences and their implications in opioid use and abuse, pain control, and susceptibility and remyelinating capacity in demyelinating disease as multiple sclerosis.


Assuntos
Encéfalo/metabolismo , Oligodendroglia/metabolismo , Peptídeos Opioides/metabolismo , Fatores Sexuais , Analgésicos Opioides/metabolismo , Analgésicos Opioides/farmacologia , Animais , Encéfalo/crescimento & desenvolvimento , Ratos Sprague-Dawley , Receptores Opioides/metabolismo , Receptores Opioides mu/metabolismo
4.
PLoS Biol ; 17(10): e3000492, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31626642

RESUMO

Naturally occurring cell death is a fundamental developmental mechanism for regulating cell numbers and sculpting developing organs. This is particularly true in the nervous system, where large numbers of neurons and oligodendrocytes are eliminated via apoptosis during normal development. Given the profound impact of death upon these two major cell populations, it is surprising that developmental death of another major cell type-the astrocyte-has rarely been studied. It is presently unclear whether astrocytes are subject to significant developmental death, and if so, how it occurs. Here, we address these questions using mouse retinal astrocytes as our model system. We show that the total number of retinal astrocytes declines by over 3-fold during a death period spanning postnatal days 5-14. Surprisingly, these astrocytes do not die by apoptosis, the canonical mechanism underlying the vast majority of developmental cell death. Instead, we find that microglia engulf astrocytes during the death period to promote their developmental removal. Genetic ablation of microglia inhibits astrocyte death, leading to a larger astrocyte population size at the end of the death period. However, astrocyte death is not completely blocked in the absence of microglia, apparently due to the ability of astrocytes to engulf each other. Nevertheless, mice lacking microglia showed significant anatomical changes to the retinal astrocyte network, with functional consequences for the astrocyte-associated vasculature leading to retinal hemorrhage. These results establish a novel modality for naturally occurring cell death and demonstrate its importance for the formation and integrity of the retinal gliovascular network.


Assuntos
Astrócitos/citologia , Morte Celular/genética , Microglia/citologia , Retina/citologia , Animais , Animais Recém-Nascidos , Astrócitos/efeitos dos fármacos , Astrócitos/metabolismo , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Vasos Sanguíneos/metabolismo , Vasos Sanguíneos/fisiopatologia , Comunicação Celular , Contagem de Células , Toxina Diftérica/toxicidade , Regulação da Expressão Gênica no Desenvolvimento , Genes Reporter , Proteína Glial Fibrilar Ácida/genética , Proteína Glial Fibrilar Ácida/metabolismo , Proteínas Luminescentes/genética , Proteínas Luminescentes/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Microglia/efeitos dos fármacos , Microglia/metabolismo , Fator de Transcrição PAX2/genética , Fator de Transcrição PAX2/metabolismo , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/genética , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/metabolismo , Retina/efeitos dos fármacos , Retina/metabolismo , Hemorragia Retiniana/genética , Hemorragia Retiniana/metabolismo , Hemorragia Retiniana/fisiopatologia , Fatores de Transcrição SOX9/genética , Fatores de Transcrição SOX9/metabolismo , Transdução de Sinais , Fator A de Crescimento do Endotélio Vascular/genética , Fator A de Crescimento do Endotélio Vascular/metabolismo
5.
Glia ; 65(12): 2003-2023, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-28906039

RESUMO

Our previous results showed that oligodendrocyte development is regulated by both nociceptin and its G-protein coupled receptor, the nociceptin/orphanin FQ receptor (NOR). The present in vitro and in vivo findings show that nociceptin plays a crucial conserved role regulating the levels of the glutamate/aspartate transporter GLAST/EAAT1 in both human and rodent brain astrocytes. This nociceptin-mediated response takes place during a critical developmental window that coincides with the early stages of astrocyte maturation. GLAST/EAAT1 upregulation by nociceptin is mediated by NOR and the downstream participation of a complex signaling cascade that involves the interaction of several kinase systems, including PI-3K/AKT, mTOR, and JAK. Because GLAST is the main glutamate transporter during brain maturation, these novel findings suggest that nociceptin plays a crucial role in regulating the function of early astrocytes and their capacity to support glutamate homeostasis in the developing brain.


Assuntos
Sistema X-AG de Transporte de Aminoácidos/metabolismo , Astrócitos/metabolismo , Regulação da Expressão Gênica no Desenvolvimento/genética , Peptídeos Opioides/metabolismo , Receptores Opioides/deficiência , Família Aldeído Desidrogenase 1 , Animais , Animais Recém-Nascidos , Astrócitos/efeitos dos fármacos , Células Cultivadas , Inibidores Enzimáticos/farmacologia , Feto/citologia , Proteína Glial Fibrilar Ácida/metabolismo , Ácido Glutâmico/metabolismo , Humanos , Hidroxilaminas/farmacologia , Camundongos Knockout , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Peptídeos Opioides/farmacologia , Ratos , Ratos Sprague-Dawley , Receptores Opioides/genética , Retinal Desidrogenase/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia , Receptor de Nociceptina , Nociceptina
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