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1.
J Neurosci ; 40(45): 8669-8682, 2020 11 04.
Artigo em Inglês | MEDLINE | ID: mdl-33046550

RESUMO

Serotonergic neurons in the dorsal raphe (DR) nucleus are associated with several psychiatric disorders including depression and anxiety disorders, which often have a neurodevelopmental component. During embryonic development, GATA transcription factors GATA2 and GATA3 operate as serotonergic neuron fate selectors and regulate the differentiation of serotonergic neuron subtypes of DR. Here, we analyzed the requirement of GATA cofactor ZFPM1 in the development of serotonergic neurons using Zfpm1 conditional mouse mutants. Our results demonstrated that, unlike the GATA factors, ZFPM1 is not essential for the early differentiation of serotonergic precursors in the embryonic rhombomere 1. In contrast, in perinatal and adult male and female Zfpm1 mutants, a lateral subpopulation of DR neurons (ventrolateral part of the DR) was lost, whereas the number of serotonergic neurons in a medial subpopulation (dorsal region of the medial DR) had increased. Additionally, adult male and female Zfpm1 mutants had reduced serotonin concentration in rostral brain areas and displayed increased anxiety-like behavior. Interestingly, female Zfpm1 mutant mice showed elevated contextual fear memory that was abolished with chronic fluoxetine treatment. Altogether, these results demonstrate the importance of ZFPM1 for the development of DR serotonergic neuron subtypes involved in mood regulation. It also suggests that the neuronal fate selector function of GATAs is modulated by their cofactors to refine the differentiation of neuronal subtypes.SIGNIFICANCE STATEMENT Predisposition to anxiety disorders has both a neurodevelopmental and a genetic basis. One of the brainstem nuclei involved in the regulation of anxiety is the dorsal raphe, which contains different subtypes of serotonergic neurons. We show that inactivation of a transcriptional cofactor ZFPM1 in mice results in a developmental failure of laterally located dorsal raphe serotonergic neurons and changes in serotonergic innervation of rostral brain regions. This leads to elevated anxiety-like behavior and contextual fear memory, alleviated by chronic fluoxetine treatment. Our work contributes to understanding the neurodevelopmental mechanisms that may be disturbed in the anxiety disorder.


Assuntos
Ansiedade/genética , Ansiedade/psicologia , Núcleo Dorsal da Rafe/crescimento & desenvolvimento , Fatores de Transcrição GATA/genética , Neurônios Serotoninérgicos , Fatores de Transcrição/genética , Animais , Comportamento Animal , Química Encefálica/genética , Núcleo Dorsal da Rafe/citologia , Medo/psicologia , Feminino , Fluoxetina/farmacologia , Masculino , Memória , Camundongos , Camundongos Knockout , Mutação/genética , Gravidez , Serotonina/metabolismo , Inibidores Seletivos de Recaptação de Serotonina/farmacologia
2.
Cell Rep ; 33(2): 108268, 2020 10 13.
Artigo em Inglês | MEDLINE | ID: mdl-33053343

RESUMO

Tegmental nuclei in the ventral midbrain and anterior hindbrain control motivated behavior, mood, memory, and movement. These nuclei contain inhibitory GABAergic and excitatory glutamatergic neurons, whose molecular diversity and development remain largely unraveled. Many tegmental neurons originate in the embryonic ventral rhombomere 1 (r1), where GABAergic fate is regulated by the transcription factor (TF) Tal1. We used single-cell mRNA sequencing of the mouse ventral r1 to characterize the Tal1-dependent and independent neuronal precursors. We describe gene expression dynamics during bifurcation of the GABAergic and glutamatergic lineages and show how active Notch signaling promotes GABAergic fate selection in post-mitotic precursors. We identify GABAergic precursor subtypes that give rise to distinct tegmental nuclei and demonstrate that Sox14 and Zfpm2, two TFs downstream of Tal1, are necessary for the differentiation of specific tegmental GABAergic neurons. Our results provide a framework for understanding the development of cellular diversity in the tegmental nuclei.


Assuntos
Neurônios GABAérgicos/metabolismo , Ácido Glutâmico/metabolismo , Rombencéfalo/metabolismo , Tegmento Mesencefálico/metabolismo , Animais , Diferenciação Celular , Linhagem da Célula , Proteínas de Ligação a DNA/metabolismo , Núcleo Dorsal da Rafe/metabolismo , Embrião de Mamíferos/citologia , Feminino , Proteína Forkhead Box O1/metabolismo , Proteínas de Homeodomínio/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Células-Tronco Neurais/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Receptores Notch/metabolismo , Fatores de Transcrição SOXB2/metabolismo , Transdução de Sinais/efeitos dos fármacos , Proteína 1 de Leucemia Linfocítica Aguda de Células T/metabolismo , Fatores de Transcrição/metabolismo
3.
Dev Neurobiol ; 78(4): 374-390, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29380551

RESUMO

Autosomal recessive disorders such as Fukuyama congenital muscular dystrophy, Walker-Warburg syndrome, and the muscle-eye-brain disease are characterized by defects in the development of patient's brain, eyes, and skeletal muscles. These syndromes are accompanied by brain malformations like type II lissencephaly in the cerebral cortex with characteristic overmigrations of neurons through the breaches of the pial basement membrane. The signaling pathways activated by laminin receptors, dystroglycan and integrins, control the integrity of the basement membrane, and their malfunctioning may underlie the pathologies found in the rise of defects reminiscent of these syndromes. Similar defects in corticogenesis and neuromuscular disorders were found in mice when RIC8A was specifically removed from neural precursor cells. RIC8A regulates a subset of G-protein α subunits and in several model organisms, it has been reported to participate in the control of cell division, signaling, and migration. Here, we studied the role of RIC8A in the development of the brain, muscles, and eyes of the neural precursor-specific conditional Ric8a knockout mice. The absence of RIC8A severely affected the attachment and positioning of radial glial processes, Cajal-Retzius' cells, and the arachnoid trabeculae, and these mice displayed additional defects in the lens, skeletal muscles, and heart development. All the discovered defects might be linked to aberrancies in cell adhesion and migration, suggesting that RIC8A has a crucial role in the regulation of cell-extracellular matrix interactions and that its removal leads to the phenotype characteristic to type II lissencephaly-associated diseases. © 2018 Wiley Periodicals, Inc. Develop Neurobiol 78: 374-390, 2018.


Assuntos
Encéfalo/embriologia , Olho/embriologia , Fatores de Troca do Nucleotídeo Guanina/deficiência , Músculos/embriologia , Células-Tronco Neurais/metabolismo , Animais , Encéfalo/metabolismo , Encéfalo/patologia , Olho/metabolismo , Olho/patologia , Fatores de Troca do Nucleotídeo Guanina/genética , Camundongos Endogâmicos C57BL , Camundongos Knockout , Músculos/metabolismo , Músculos/patologia , Células-Tronco Neurais/patologia
4.
Development ; 143(23): 4495-4508, 2016 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-27789623

RESUMO

Serotonergic and glutamatergic neurons of the dorsal raphe regulate many brain functions and are important for mental health. Their functional diversity is based on molecularly distinct subtypes; however, the development of this heterogeneity is poorly understood. We show that the ventral neuroepithelium of mouse anterior hindbrain is divided into specific subdomains giving rise to serotonergic neurons as well as other types of neurons and glia. The newly born serotonergic precursors are segregated into distinct subpopulations expressing vesicular glutamate transporter 3 (Vglut3) or serotonin transporter (Sert). These populations differ in their requirements for transcription factors Gata2 and Gata3, which are activated in the post-mitotic precursors. Gata2 operates upstream of Gata3 as a cell fate selector in both populations, whereas Gata3 is important for the differentiation of the Sert+ precursors and for the serotonergic identity of the Vglut3+ precursors. Similar to the serotonergic neurons, the Vglut3-expressing glutamatergic neurons, located in the central dorsal raphe, are derived from neural progenitors in the ventral hindbrain and express Pet1 Furthermore, both Gata2 and Gata3 are redundantly required for their differentiation. Our study demonstrates lineage relationships of the dorsal raphe neurons and suggests that functionally significant heterogeneity of these neurons is established early during their differentiation.


Assuntos
Núcleo Dorsal da Rafe/citologia , Fator de Transcrição GATA2/genética , Fator de Transcrição GATA3/genética , Neurogênese/genética , Rombencéfalo/embriologia , Neurônios Serotoninérgicos/citologia , Sistemas de Transporte de Aminoácidos Acídicos/metabolismo , Animais , Camundongos , Camundongos Knockout , Células-Tronco Neurais/citologia , Neurogênese/fisiologia , Neuroglia/citologia , Rombencéfalo/fisiologia , Proteínas da Membrana Plasmática de Transporte de Serotonina/metabolismo , Inibidores da Recaptação de Serotonina e Norepinefrina/farmacologia , Fatores de Transcrição/biossíntese
5.
Development ; 143(3): 516-29, 2016 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-26718003

RESUMO

Local inhibitory GABAergic and excitatory glutamatergic neurons are important for midbrain dopaminergic and hindbrain serotonergic pathways controlling motivation, mood, and voluntary movements. Such neurons reside both within the dopaminergic nuclei, and in adjacent brain structures, including the rostromedial and laterodorsal tegmental nuclei. Compared with the monoaminergic neurons, the development, heterogeneity, and molecular characteristics of these regulatory neurons are poorly understood. We show here that different GABAergic and glutamatergic subgroups associated with the monoaminergic nuclei express specific transcription factors. These neurons share common origins in the ventrolateral rhombomere 1, where the postmitotic selector genes Tal1, Gata2 and Gata3 control the balance between the generation of inhibitory and excitatory neurons. In the absence of Tal1, or both Gata2 and Gata3, the GABAergic precursors adopt glutamatergic fates and populate the glutamatergic nuclei in excessive numbers. Together, our results uncover developmental regulatory mechanisms, molecular characteristics, and heterogeneity of central regulators of monoaminergic circuits.


Assuntos
Diferenciação Celular , Núcleo Celular/metabolismo , Neurônios Dopaminérgicos/citologia , Mesencéfalo/citologia , Inibição Neural , Animais , Biomarcadores/metabolismo , Galinhas , Embrião de Mamíferos/metabolismo , Feminino , Fatores de Transcrição Forkhead/metabolismo , Neurônios GABAérgicos/citologia , Fatores de Transcrição GATA/metabolismo , Glutamatos/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos ICR , Mitose , Modelos Biológicos , Proteínas Repressoras/metabolismo , Serotonina/metabolismo , Substância Negra/citologia , Área Tegmentar Ventral/citologia , Ácido gama-Aminobutírico/metabolismo
6.
Dev Neurobiol ; 75(9): 984-1002, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-25641781

RESUMO

RIC8A is a noncanonical guanine nucleotide exchange factor for a subset of Gα subunits. RIC8A has been reported in different model organisms to participate in the control of mitotic cell division, cell signalling, development and cell migration. Still, the function of RIC8A in the mammalian nervous system has not been sufficiently analysed yet. Adult mice express RIC8A in the brain regions involved in the regulation of memory and emotional behaviour. To elucidate the role of RIC8A in mammalian neurogenesis we have inactivated Ric8a in neural precursor cells using Cre/Lox system. As a result, the conditional knockout mice were born at expected Mendelian ratio, but died or were cannibalized by their mother within 12 h after birth. The cerebral cortex of the newborn Nes;Ric8a(CKO) mice was thinner compared to littermates and the basement membrane was discontinuous, enabling migrating neurons to invade to the marginal zone. In addition, the balance between the planar and oblique cell divisions was altered, influencing the neuron production. Taken together, RIC8A has an essential role in the development of mammalian nervous system by maintaining the integrity of pial basement membrane and modulating cell division.


Assuntos
Fatores de Troca do Nucleotídeo Guanina/metabolismo , Células-Tronco Neurais/fisiologia , Neurogênese/fisiologia , Doenças Neuromusculares/fisiopatologia , Neurônios/fisiologia , Animais , Animais Recém-Nascidos , Western Blotting , Movimento Celular/fisiologia , Córtex Cerebral/patologia , Córtex Cerebral/fisiopatologia , Morte , Fatores de Troca do Nucleotídeo Guanina/genética , Imageamento Tridimensional , Imuno-Histoquímica , Hibridização In Situ , Camundongos Endogâmicos C57BL , Camundongos Knockout , Células-Tronco Neurais/patologia , Doenças Neuromusculares/mortalidade , Doenças Neuromusculares/patologia , Neurônios/patologia , Reação em Cadeia da Polimerase em Tempo Real
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