Neural Development最新文献

In the mammalian cerebral cortex neurons are arranged in specific layers and form connections both within the cortex and with other brain regions, thus forming a complex mesh of specialized synaptic connections comprising distinct circuits. The correct establishment of these connections during development is crucial for the proper function of the brain. Astrocytes, a major type of glial cell, are important regulators of synapse formation and function during development. While neurogenesis precedes astrogenesis in the cortex, neuronal synapses only begin to form after astrocytes have been generated, concurrent with neuronal branching and process elaboration. Here we provide a combined overview of the developmental processes of synapse and circuit formation in the rodent cortex, emphasizing the timeline of both neuronal and astrocytic development and maturation. We further discuss the role of astrocytes at the synapse, focusing on astrocyte-synapse contact and the role of synapse-related proteins in promoting formation of distinct cortical circuits.

More than 30 years of studies into Drosophila melanogaster neurogenesis have revealed fundamental insights into our understanding of axon guidance mechanisms, neural differentiation, and early cell fate decisions. What is less understood is how a group of neurons from disparate anterior-posterior axial positions, lineages and developmental periods of neurogenesis coalesce to form a functional circuit. Using neurogenetic techniques developed in Drosophila it is now possible to study the neural substrates of behavior at single cell resolution. New mapping tools described in this review, allow researchers to chart neural connectivity to better understand how an anatomically simple organism performs complex behaviors.

Brain function requires precise neural circuit assembly during development. Establishing a functional circuit involves multiple coordinated steps ranging from neural cell fate specification to proper matching between pre- and post-synaptic partners. How neuronal lineage and birth timing influence wiring specificity remains an open question. Recent findings suggest that the relationships between lineage, birth timing, and wiring specificity vary in different neuronal circuits. In this review, we summarize our current understanding of the cellular, molecular, and developmental mechanisms linking neuronal lineage and birth timing to wiring specificity in a few specific systems in Drosophila and mice, and review different methods employed to explore these mechanisms.

Background: Activity in neurons drives afferent competition that is critical for the refinement of nascent neural circuits. In ferrets, when an eye is lost in early development, surviving retinogeniculate afferents from the spared eye spread across the thalamus in a manner that is dependent on spontaneous retinal activity. However, how this spontaneous activity, also known as retinal waves, might dynamically regulate afferent terminal targeting remains unknown.

Methods: We recorded retinal waves from retinae ex vivo using multi-electrode arrays. Retinae came from ferrets who were binocular or who had one eye surgically removed at birth. Linear mixed effects models were used to investigate the effects of early monocular enucleation on retinal wave activity.

Results: When an eye is removed at birth, spontaneous bursts of action potentials by retinal ganglion cells (RGCs) in the surviving eye are shorter in duration. The shortening of RGC burst duration results in decreased pairwise RGC correlations across the retina and is associated with the retinal wave-dependent spread of retinogeniculate afferents previously reported in enucleates.

Conclusion: Our findings show that removal of the competing eye modulates retinal waves and could underlie the dynamic regulation of competition-based refinement during retinogeniculate development.

Background: Most oligodendrocytes of the spinal cord originate from ventral progenitor cells of the pMN domain, characterized by expression of the transcription factor Olig2. A minority of oligodendrocytes is also recognized to emerge from dorsal progenitors during fetal development. The prevailing view is that generation of ventral oligodendrocytes depends on Sonic hedgehog (Shh) while dorsal oligodendrocytes develop under the influence of Fibroblast Growth Factors (FGFs).

Results: Using the well-established model of the chicken embryo, we show that ventral spinal progenitor cells activate FGF signaling at the onset of oligodendrocyte precursor cell (OPC) generation. Inhibition of FGF receptors at that time appears sufficient to prevent generation of ventral OPCs, highlighting that, in addition to Shh, FGF signaling is required also for generation of ventral OPCs. We further reveal an unsuspected interplay between Shh and FGF signaling by showing that FGFs serve dual essential functions in ventral OPC specification. FGFs are responsible for timely induction of a secondary Shh signaling center, the lateral floor plate, a crucial step to create the burst of Shh required for OPC specification. At the same time, FGFs prevent down-regulation of Olig2 in pMN progenitor cells as these cells receive higher threshold of the Shh signal. Finally, we bring arguments favoring a key role of newly differentiated neurons acting as providers of the FGF signal required to trigger OPC generation in the ventral spinal cord.

Conclusion: Altogether our data reveal that the FGF signaling pathway is activated and required for OPC commitment in the ventral spinal cord. More generally, our data may prove important in defining strategies to produce large populations of determined oligodendrocyte precursor cells from undetermined neural progenitors, including stem cells. In the long run, these new data could be useful in attempts to stimulate the oligodendrocyte fate in residing neural stem cells.

Background: Radial glial stem cells within the developing nervous system generate a variety of post-mitotic cells, including neurons and glial cells, as well as the specialised multi-ciliated cells that line the walls of the ventricular system, the ependymal cells. Ependymal cells separate the brain parenchyma from the cerebrospinal fluid and mediate osmotic regulation, the flow of cerebrospinal fluid, and the subsequent dispersion of signalling molecules via the co-ordinated beating of their cilia. Deficits to ependymal cell development and function have been implicated in the formation of hydrocephalus, but the transcriptional mechanisms underpinning ependymal development remain poorly characterised.

Findings: Here, we demonstrate that the transcription factor nuclear factor IX (NFIX) plays a central role in the development of the ependymal cell layer of the lateral ventricles. Expression of ependymal cell-specific markers is delayed in the absence of Nfix. Moreover, Nfix-deficient mice exhibit aberrant ependymal cell morphology at postnatal day 15, culminating in abnormal thickening and intermittent loss of this cell layer. Finally, we reveal Foxj1, a key factor promoting ependymal cell maturation, as a target for NFIX-mediated transcriptional activation.

Conclusions: Collectively, our data indicate that ependymal cell development is reliant, at least in part, on NFIX expression, further implicating this transcription factor as a mediator of multiple aspects of radial glial biology during corticogenesis.

Correction: After publication of the original article [1] it was realised that there were errors in figures 2a,b,f,g, which arose as a result of preparing figures from data collected and analysed at the same time as the work reported in [2] (Supplementary Figure 1 of [2]). An updated Fig. 2 is included with this Correction.

Background: Olfactory bulb (OB) interneurons are known to represent diverse neuronal subtypes, which are thought to originate from a number of telencephalic regions including the embryonic dorsal lateral ganglionic eminence (dLGE) and septum. These cells migrate rostrally toward the OB, where they then radially migrate to populate different OB layers including the granule cell layer (GCL) and the outer glomerular layer (GL). Although previous studies have attempted to investigate regional contributions to OB interneuron diversity, few genetic tools have been used to address this question at embryonic time points when the earliest populations are specified.

Methods: In this study, we utilized Zic3-lacZ and Gsx2e-CIE transgenic mice as genetic fate-mapping tools to study OB interneuron contributions derived from septum and LGE, respectively. Moreover, to address the regional (i.e. septal) requirements of the homeobox gene Gsx2 for OB interneuron diversity, we conditionally inactivated Gsx2 in the septum, leaving it largely intact in the dLGE, by recombining the Gsx2 floxed allele using Olig2 ^Cre/+ mice.

Results: Our fate mapping studies demonstrated that the dLGE and septum gave rise to OB interneuron subtypes differently. Notably, the embryonic septum was found to give rise largely to the calretinin⁺ (CR⁺) GL subtype, while the dLGE was more diverse, generating all major GL subpopulations as well as many GCL interneurons. Moreover, Gsx2 conditional mutants (cKOs), with septum but not dLGE recombination, showed impaired generation of CR⁺ interneurons within the OB GL. These Gsx2 cKOs exhibited reduced proliferation within the septal subventricular zone (SVZ), which correlated well with the reduced number of CR⁺ interneurons observed.

Conclusions: Our findings indicate that the septum and LGE contribute differently to OB interneuron diversity. While the dLGE provides a wide range of OB interneuron subtypes, the septum is more restricted in its contribution to the CR⁺ subtype. Gsx2 is required in septal progenitors for the correct expansion of SVZ progenitors specified toward the CR⁺ subtype. Finally, the septum has been suggested to be the exclusive source of CR⁺ interneurons in postnatal studies. Our results here demonstrate that dLGE progenitors in the embryo also contribute to this OB neuronal subtype.