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1.
J Neurosci ; 42(16): 3344-3364, 2022 04 20.
Artigo em Inglês | MEDLINE | ID: mdl-35273083

RESUMO

The projection neurons of the striatum, the principal nucleus of the basal ganglia, belong to one of the following two major pathways: the striatopallidal (indirect) pathway or the striatonigral (direct) pathway. Striatonigral axons project long distances and encounter ascending tracts (thalamocortical) while coursing alongside descending tracts (corticofugal) as they extend through the internal capsule and cerebral peduncle. These observations suggest that striatal circuitry may help to guide their trajectories. To investigate the developmental contributions of striatonigral axons to internal capsule formation, we have made use of Sox8-EGFP (striatal direct pathway) and Fezf2-TdTomato (corticofugal pathway) BAC transgenic reporter mice in combination with immunohistochemical markers to trace these axonal pathways throughout development. We show that striatonigral axons pioneer the internal capsule and cerebral peduncle and are temporally and spatially well positioned to provide guidance for corticofugal and thalamocortical axons. Using Isl1 conditional knock-out (cKO) mice, which exhibit disrupted striatonigral axon outgrowth, we observe both corticofugal and thalamocortical axon defects with either ventral forebrain- or telencephalon-specific Isl1 inactivation, despite Isl1 not being expressed in either cortical or thalamic projection neurons. Striatonigral axon defects can thus disrupt internal capsule formation. Our genome-wide transcriptomic analysis in Isl1 cKOs reveals changes in gene expression relevant to cell adhesion, growth cone dynamics, and extracellular matrix composition, suggesting potential mechanisms by which the striatonigral pathway exerts this guidance role. Together, our data support a novel pioneering role for the striatal direct pathway in the correct assembly of the ascending and descending axon tracts within the internal capsule and cerebral peduncle.SIGNIFICANCE STATEMENT The basal ganglia are a group of subcortical nuclei with established roles in the coordination of voluntary motor programs, aspects of cognition, and the selection of appropriate social behaviors. Hence, disruptions in basal ganglia connectivity have been implicated in the motor, cognitive, and social dysfunction characterizing common neurodevelopmental disorders such as attention-deficit/hyperactivity disorder, autism spectrum disorder, obsessive-compulsive disorder, and tic disorder. Here, we identified a novel role for the striatonigral (direct) pathway in pioneering the internal capsule and cerebral peduncle, and in guiding axons extending to and from the cortex. Our findings suggest that the abnormal development of basal ganglia circuits can drive secondary internal capsule defects and thereby may contribute to the pathology of these disorders.


Assuntos
Transtorno do Espectro Autista , Pedúnculo Cerebral , Animais , Transtorno do Espectro Autista/metabolismo , Axônios/fisiologia , Córtex Cerebral/metabolismo , Cápsula Interna , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Vias Neurais/fisiologia , Tálamo
2.
Nat Commun ; 9(1): 4725, 2018 11 09.
Artigo em Inglês | MEDLINE | ID: mdl-30413696

RESUMO

The striatum controls behaviors via the activity of direct and indirect pathway projection neurons (dSPN and iSPN) that are intermingled in all compartments. While such cellular mosaic ensures the balanced activity of the two pathways, its developmental origin and pattern remains largely unknown. Here, we show that both SPN populations are specified embryonically and intermix progressively through multidirectional iSPN migration. Using conditional mutant mice, we found that inactivation of the dSPN-specific transcription factor Ebf1 impairs selective dSPN properties, including axon pathfinding, while molecular and functional features of iSPN were preserved. Ebf1 mutation disrupted iSPN/dSPN intermixing, resulting in an uneven distribution. Such architectural defect was selective of the matrix compartment, highlighting that intermixing is a parallel process to compartment formation. Our study reveals while iSPN/dSPN specification is largely independent, their intermingling emerges from an active migration of iSPN, thereby providing a novel framework for the building of striatal architecture.


Assuntos
Neostriado/fisiologia , Neurônios/fisiologia , Animais , Diferenciação Celular , Movimento Celular , Embrião de Mamíferos/fisiologia , Deleção de Genes , Camundongos Endogâmicos C57BL , Neostriado/embriologia , Neurônios/citologia , Transativadores/deficiência , Transativadores/metabolismo
3.
J Comp Neurol ; 525(13): 2805-2819, 2017 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-28472858

RESUMO

The striatum is the major component of the basal ganglia and is well known to play a key role in the control of motor function via balanced output from the indirect (iSPNs) and direct pathway striatal projection neurons (dSPNs). Little is known, however, about the molecular genetic mechanisms that control the formation of the iSPNs versus dSPNs. We show here that the SoxE family member, Sox8, is co-expressed with the dSPN markers, Isl1 and Ebf1, in the developing striatum. Moreover, dSPNs, as marked by Isl1-cre fate map, express Sox8 in the embryonic striatum and Sox8-EGFP BAC transgenic mice specifically reveal the direct pathway axons during development. These EGFP+ axons are first observed to reach their midbrain target, the substantia nigra pars reticulata (SNr), at E14 in the mouse with a robust connection observed already at birth. The selective expression of EGFP in dSPNs of Sox8-EGFP BAC mice is maintained at postnatal timepoints. Sox8 is known to be expressed in oligodendrocyte precursor cells (OPCs) together with other SoxE factors and we show here that the EGFP signal co-localizes with the OPC markers throughout the brain. Finally, we show that Sox8-EGFP BAC mice can be used to interrogate the altered dSPN development in Isl1 conditional mutants including aberrant axonal projections detected already at embryonic timepoints. Thus, Sox8 represents an early and specific marker of embryonic dSPNs and the Sox8-EGFP BAC transgenic mice are an excellent tool to study the development of basal ganglia circuitry.


Assuntos
Corpo Estriado , Regulação da Expressão Gênica no Desenvolvimento/fisiologia , Vias Neurais/fisiologia , Neurônios/metabolismo , Fatores de Transcrição SOXE/metabolismo , Transdução de Sinais/fisiologia , Animais , Animais Recém-Nascidos , Corpo Estriado/citologia , Corpo Estriado/embriologia , Corpo Estriado/crescimento & desenvolvimento , Corpo Estriado/metabolismo , Embrião de Mamíferos , Fatores de Transcrição Forkhead/metabolismo , Regulação da Expressão Gênica no Desenvolvimento/genética , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Proteínas com Homeodomínio LIM/genética , Proteínas com Homeodomínio LIM/metabolismo , Camundongos , Camundongos Transgênicos , Mutação/genética , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Receptores de Dopamina D1/genética , Receptores de Dopamina D1/metabolismo , Receptores de Dopamina D2/genética , Receptores de Dopamina D2/metabolismo , Proteínas Repressoras/metabolismo , Fatores de Transcrição SOXE/genética , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo
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