Development of oligodendrocytes, myelin-forming glia in the central nervous system (CNS), proceeds on a protracted schedule. Specification of oligodendrocyte progenitor cells (OPCs) begins early in development, whereas their terminal differentiation occurs at late embryonic and postnatal periods. However, for oligodendrocytes in the cerebellum, the developmental origins and the molecular machinery to control these distinct steps remain unclear. By in vivo fate mapping and immunohistochemical analyses, we obtained evidence that the majority of oligodendrocytes in the cerebellum originate from the Olig2-expressing neuroepithelial domain in the ventral rhombomere 1 (r1), while about 6% of cerebellar oligodendrocytes are produced in the cerebellar ventricular zone. Furthermore, to elucidate the molecular determinants that regulate their development, we analyzed mice in which the transcription factor Sox9 was specifically ablated from the cerebellum, ventral r1 and caudal midbrain by means of the Cre/loxP recombination system. This resulted in a delay in the birth of OPCs and subsequent developmental aberrations in these cells in the Sox9-deficient mice. In addition, we observed altered proliferation of OPCs, resulting in a decrease in oligodendrocyte numbers that accompanied an attenuation of the differentiation and an increased rate of apoptosis. Results from in vitro assays using oligodendrocyte-enriched cultures further supported our observations from in vivo experiments. These data suggest that Sox9 participates in the development of oligodendrocytes in the cerebellum, by regulating the timing of their generation, proliferation, differentiation and survival.
The layer structure has been intensively characterized in the developing neocortex and cerebellum based on the various molecular markers. However, as to the developing dorsal midbrain, comprehensive analyses have not been intensely carried out, and thus, the name as well as the definition of each layer is not commonly shared.Here, we redefined the three layers, such as the ventricular zone, intermediate zone and marginal zone, based on various markers for proliferation and differentiation in embryonic dorsal midbrain. Biphasic Ki67 expression defines the classical VZ, in which there is clear separation of the mitotic and interphase zones. Next, we mapped the distribution of immature neurons to the defined layers, based on markers for glutamatergic and GABAergic lineage. Interestingly, Tbr2 and Neurog2 were expressed in the postmitotic neurons. We also report that active (phosphorylated) JNK is a useful marker to demarcate layers during the embryonic stage. Finally, we validated the final arrival layers of the migratory glutamatergic and GABAergic neurons. These results form a foundation for analyses of brain development, especially in the proliferation and migration of excitatory and inhibitory neurons in the dorsal midbrain.
Chronic stress increases the risk of developing psychiatric disorders, including mood and anxiety disorders. Although behavioral responses to repeated stress vary across individuals, the underlying mechanisms remain unclear. Here, we perform a genome-wide transcriptome analysis of an animal model of depression and patients with clinical depression and report that dysfunction of the Fos-mediated transcription network in the anterior cingulate cortex (ACC) confers a stress-induced social interaction deficit. Critically, CRISPR-Cas9–mediated ACC Fos knockdown causes social interaction deficits under stressful situation. Moreover, two classical second messenger pathways, calcium and cyclic AMP, in the ACC during stress differentially modulate Fos expression and regulate stress-induced changes in social behaviors. Our findings highlight a behaviorally relevant mechanism for the regulation of calcium- and cAMP-mediated Fos expression that has potential as a therapeutic target for psychiatric disorders related to stressful environments.
The cerebellum represents a good model system to investigate the molecular machinery underlying the synapse development, including its initiation, maturation and elimination depending on the neuronal activity. Multiple climbing fibers (CFs, axons of Inferior olivary neurons) innervate single purkinje cell soma and make synaptic-contact in early developmental stage. As advance the stage, single CF (Winner-CF) strengthened depend on neural activity. This Winner-CF translocates to PC dendrites and makes more synapses at P9 and later developmental stage. On the other hand, other weak CFs are pruned. These synapse formation mechanisms are important to neural circuit and brain function. However, its molecular mechanisms are unrevealed. We show that Down's syndrome relation molecule (DSCAM) has an important role for CF synapse formation in cerebellum. 1) DSCAM was expressed at cerebellar neuron and glia. 2) vGluT2 puncta (CF synapses) were decreased in adult Dscam mutant mouse. 3) The relative height of vGluT2 puncta decreased in adult mutant mouse. 4) Bergmann glia processes were inaccessible to active zone of synapses at outer molecular layer in Dscam mutant mouse. 5) Synapse size and post synaptic density (PSD) length at outer molecular layer were shorter in Dscam mutant mouse. These results suggest that DSCAM plays the important roles for CF synapse formation.
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