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The spatial and temporal linear expression of Hox genes establishes a regional Hox code, which is crucial for the antero-posterior (A-P) patterning, segmentation, and neuronal circuit development of the hindbrain. RNF220, an E3 ubiquitin ligase, is widely involved in neural development via targeting of multiple substrates. Here, we found that the expression of Hox genes in the pons was markedly up-regulated at the late developmental stage (post-embryonic day E15.5) in Rnf220 -/- and Rnf220 +/- mouse embryos. Single-nucleus RNA sequencing (RNA-seq) analysis revealed different Hox de-repression profiles in different groups of neurons, including the pontine nuclei (PN). The Hox pattern was disrupted and the neural circuits were affected in the PN of Rnf220 +/- mice. We showed that this phenomenon was mediated by WDR5, a key component of the TrxG complex, which can be polyubiquitinated and degraded by RNF220. Intrauterine injection of WDR5 inhibitor (WDR5-IN-4) and genetic ablation of Wdr5 in Rnf220 +/- mice largely recovered the de-repressed Hox expression pattern in the hindbrain. In P19 embryonal carcinoma cells, the retinoic acid-induced Hox expression was further stimulated by Rnf220 knockdown, which can also be rescued by Wdr5 knockdown. In short, our data suggest a new role of RNF220/WDR5 in Hox pattern maintenance and pons development in mice.

Alzheimer’s disease (AD) is characterized by progressive synaptic dysfunction, neuronal death, and brain atrophy, with amyloid-β (Aβ) plaque deposits and hyperphosphorylated tau neurofibrillary tangle accumulation in the brain tissue, which all lead to loss of cognitive function. Pathogenic mutations in the well-known AD causal genes including APP , PSEN1 , and PSEN2 impair a variety of pathways, including protein processing, axonal transport, and metabolic homeostasis. Here we identified a missense variant rs117916664 (c.896T>C, p.Asn299Ser [p.N299S]) of the acetyl-CoA acyltransferase 1 ( ACAA1 ) gene in a Han Chinese AD family by whole-genome sequencing and validated its association with early-onset familial AD in an independent cohort. Further in vitro and in vivo evidence showed that ACAA1 p.N299S contributes to AD by disturbing its enzymatic activity, impairing lysosomal function, and aggravating the Aβ pathology and neuronal loss, which finally caused cognitive impairment in a murine model. Our findings reveal a fundamental role of peroxisome-mediated lysosomal dysfunction in AD pathogenesis.

The neural fate commitment of pluripotent stem cells requires the repression of extrinsic inhibitory signals and the activation of intrinsic positive transcription factors. However, how these two events are integrated to ensure appropriate neural conversion remains unclear. In this study, we showed that Pou3f1 is essential for the neural differentiation of mouse embryonic stem cells (ESCs), specifically during the transition from epiblast stem cells (EpiSCs) to neural progenitor cells (NPCs). Chimeric analysis showed that Pou3f1 knockdown leads to a markedly decreased incorporation of ESCs in the neuroectoderm. By contrast, Pou3f1-overexpressing ESC derivatives preferentially contribute to the neuroectoderm. Genome-wide ChIP-seq and RNA-seq analyses indicated that Pou3f1 is an upstream activator of neural lineage genes, and also is a repressor of BMP and Wnt signaling. Our results established that Pou3f1 promotes the neural fate commitment of pluripotent stem cells through a dual role, activating internal neural induction programs and antagonizing extrinsic neural inhibitory signals. After an egg has been fertilized, it undergoes a series of divisions to produce a ball of cells known as a blastocyst. The cells within the blastocyst are pluripotent stem cells, which have the potential to become many different types of cell. After a few days, the stem cells organize into three layers—an innermost layer called the endoderm, a middle layer of mesoderm, and an outer layer of ectoderm—that ultimately give rise to different types of tissues. The brain and nervous system are formed from cells in the neuroectoderm, which is part of the ectoderm. Now, Zhu et al. have shown that a transcription factor called Pou3f1 triggers stem cells within a region of the ectoderm to turn into neural progenitor cells, thereby generating the neuroectoderm. These neural progenitor cells then go on to become neurons and glial cells that make up the brain and nervous system. Using a virus to reduce levels of Pou3f1 in embryonic stem cells grown in a dish led to a drop in the number of stem cells that committed to neural progenitor cells. Overexpressing Pou3f1 in the stem cells restored the number of neural progenitor cells. Together these results showed that Pou3f1 is both necessary and sufficient for the conversion of embryonic stem cells into future neurons and glia. The same result was seen when embryonic stem cells containing either reduced or elevated levels of Pou3f1 were injected into 2.5-day-old mouse blastocysts, which were then implanted into surrogate females. The resulting embryos comprised some cells with normal levels of Pou3f1, and others with either too little or too much. Cells with elevated Pou3f1 mostly became neural progenitors, whereas those with reduced levels rarely did so. Gene expression studies revealed that Pou3f1 promoted the formation of neural progenitor cells by activating the expression of pro-neuronal genes inside the stem cells, and by blocking anti-neuronal pathways called Wnt/BMP signaling cascades initiated outside the cells. By revealing the two roles of Pou3f1, Zhu et al. have increased our understanding of one of the earliest stages of nervous system development. Further work is required to determine exactly how Pou3f1 exerts its effects and, in particular, whether it performs its two roles simultaneously or in sequence.

Kainate-type glutamate receptors play critical roles in excitatory synaptic transmission and synaptic plasticity in the brain. GluK1 and GluK2 possess fundamentally different capabilities in surface trafficking as well as synaptic targeting in hippocampal CA1 neurons. Here we find that the excitatory postsynaptic currents (EPSCs) are significantly increased by the chimeric GluK1(SP GluK2 ) receptor, in which the signal peptide of GluK1 is replaced with that of GluK2. Coexpression of GluK1 signal peptide completely suppresses the gain in trafficking ability of GluK1(SP GluK2 ), indicating that the signal peptide represses receptor trafficking in a trans manner. Furthermore, we demonstrate that the signal peptide directly interacts with the amino-terminal domain (ATD) to inhibit the synaptic and surface expression of GluK1. Thus, we have uncovered a trafficking mechanism for kainate receptors and propose that the cleaved signal peptide behaves as a ligand of GluK1, through binding with the ATD, to repress forward trafficking of the receptor. The two kainate receptors GluK1 and GluK2 show different surface expression and synaptic trafficking. Here authors engineer chimeric GluK1-GluK2 receptors and decipher a role how the signal peptide of GluK1 behaves as a ligand of GluK1 and modifies surface expression and trafficking.

The missense variant rs13107325 (C/T, p.Ala391Thr) in SLC39A8 consistently showed robust association with schizophrenia in recent genome-wide association studies (GWASs), suggesting the potential pathogenicity of this non-synonymous risk variant. Nevertheless, how this missense variant confers schizophrenia risk remains unknown. Here we constructed a knock-in mouse model (by introducing a threonine at the 393th amino acid of mouse SLC39A8 (SLC39A8-p.393T), which corresponds to rs13107325 (p.Ala391Thr) of human SLC39A8) to explore the potential roles and biological effects of this missense variant in schizophrenia pathogenesis. We assessed multiple phenotypes and traits (associated with rs13107325) of the knock-in mice, including body and brain weight, concentrations of metal ions (including cadmium, zinc, manganese, and iron) transported by SLC39A8, blood lipids, proliferation and migration of neural stem cells (NSCs), cortical development, behaviors and cognition, transcriptome, dendritic spine density, and synaptic transmission. Many of the tested phenotypes did not show differences in SLC39A8-p.393T knock-in and wild-type mice. However, we found that zinc concentration in brain and blood of SLC39A8-p.393T knock-in mice was dysregulated compared with wild-types, validating the functionality of rs13107325. Further analysis indicated that cortical dendritic spine density of the SLC39A8-p.393T knock-in mice was significantly decreased compared with wild-types, indicating the important role of SLC39A8-p.393T in dendritic spine morphogenesis. These results indicated that SLC39A8-p.393T knock-in resulted in decreased dendritic spine density, thus mimicking the dendritic spine pathology observed in schizophrenia. Our study indicates that rs13107325 might confer schizophrenia risk by regulating zinc concentration and dendritic spine density, a featured characteristic that was frequently reported to be decreased in schizophrenia.

The δ1 glutamate receptor (GluD1) was cloned decades ago and is widely expressed in many regions of the brain. However, its functional roles in these brain circuits remain unclear. Here, we find that GluD1 is required for both excitatory synapse formation and maintenance in the hippocampus. The action of GluD1 is absent in the Cbln2 knockout mouse. Furthermore, the GluD1 actions require the presence of presynaptic neurexin 1β carrying the splice site 4 insert (+S4). Together, our findings demonstrate that hippocampal synapse assembly and maintenance require a tripartite molecular complex in which the ligand Cbln2 binds with presynaptic neurexin 1β (+S4) and postsynaptic GluD1. We provide evidence that this mechanism may apply to other forebrain synapses, where GluD1 is widely expressed.

The proper function of the bone morphogenic protein (BMP) pathway during embryonic development and organ maintenance requires its communication with other signaling pathways. Unlike the well-documented regulation of the BMP pathway by FGF/MAPK and Wnt/GSK3 signals, cross-talk between BMP/Smad and retinoic acid (RA)/RA receptor (RAR) pathways is poorly understood. Here, we show that RA represses BMP signal duration by reducing the level of phosphorylated Smad1 (pSmad1). Through its nuclear receptor-mediated transcription, RA enhances the interaction between pSmad1 and its ubiquitin E3 ligases, thereby promoting pSmad1 ubiquitination and proteasomal degradation. This regulation depends on the RA-increased Gadd45 expression and MAPK activation. During the neural development in chicken embryo, the RA/RAR pathway also suppresses BMP signaling to antagonize BMP-regulated proliferation and differentiation of neural progenitor cells. Furthermore, this cross-talk between RA and BMP pathways is involved in the proper patterning of dorsal neural tube of chicken embryo. Our results reveal a mechanism by which RA suppresses BMP signaling through regulation of pSmad1 stability.

Kainate receptors (KARs) are a subfamily of glutamate receptors mediating excitatory synaptic transmission and Neto proteins are recently identified auxiliary subunits for KARs. However, the roles of Neto proteins in the synaptic trafficking of KAR GluK1 are poorly understood. Here, using the hippocampal CA1 pyramidal neuron as a null background system we find that surface expression of GluK1 receptor itself is very limited and is not targeted to excitatory synapses. Both Neto1 and Neto2 profoundly increase GluK1 surface expression and also drive GluK1 to synapses. However, the regulation GluK1 synaptic targeting by Neto proteins is independent of their role in promoting surface trafficking. Interestingly, GluK1 is excluded from synapses expressing AMPA receptors and is selectively incorporated into silent synapses. Neto2, but not Neto1, slows GluK1 deactivation, whereas Neto1 speeds GluK1 desensitization and Neto2 slows desensitization. These results establish critical roles for Neto auxiliary subunits controlling KARs properties and synaptic incorporation. Information is transmitted in the brain by cells called neurons. To communicate with neighboring cells, neurons release chemicals called neurotransmitters across a structure called a synapse that forms a junction between the cells. The neurotransmitters bind to receptors on the surface of the receiving neuron, and depending on the type of neurotransmitter released, make that neuron either more or less likely to signal to its neighbors. Excitatory neurotransmitters make neurons more likely to signal, and glutamate is the most common excitatory neurotransmitter in the brain. There are several different types of receptor that can bind to glutamate, one of which – the kainate receptor – is found at relatively few synapses. These synapses include some in the hippocampus, a region of the brain that is important for memory. Researchers have recently identified two auxiliary proteins, called Neto1 and Neto2, that interact with kainate receptors and appear to affect how strongly the kainate receptors respond when glutamate binds to them. However, the effect of the Neto proteins on one particular subunit of the kainate receptors – called GluK1 – had not been investigated in depth. CA1 pyramidal neurons are a group of neurons in the hippocampus that are able to produce kainate receptors, but these receptors are not found in CA1 pyramidal neuron synapses. Sheng et al. have now studied CA1 pyramidal neurons from rats, and found that these cells produce a limited amount of GluK1 on their surfaces. However, when GluK1 is expressed together with Neto1 or Neto2, GluK1 receptors appear on the cell surface. Through an independent mechanism Neto proteins also promote the targeting of surface GluK1 to the synapse. Unexpectedly, GluK1 was excluded from synapses that contain another type of glutamate receptor called AMPA receptors. By measuring the effect of Neto1 and Neto2 on the behavior of GluK1, Sheng et al. found that these proteins modified how the receptor responded to prolonged exposure to glutamate. Specifically, Neto1 increased how quickly GluK1 became desensitized to glutamate, while Neto2 decreased the rate of desensitization. This study demonstrates that Neto proteins play critical roles in controlling the location and biophysical properties of kainate receptors. It will be of interest to see how the present findings apply to other excitatory synapses in the brain.

The δ1 glutamate receptor (GluD1) was cloned decades ago and is widely expressed in many regions of the brain. However, its functional roles in these brain circuits remain unclear. Here, we find that GluD1 is required for both excitatory synapse formation and maintenance in the hippocampus. The action of GluD1 is absent in the Cbln2 knockout mouse. Furthermore, the GluD1 actions require the presence of presynaptic neurexin 1β carrying the splice site 4 insert (+S4). Together, our findings demonstrate that hippocampal synapse assembly and maintenance require a tripartite molecular complex in which the ligand Cbln2 binds with presynaptic neurexin 1β (+S4) and postsynaptic GluD1. We provide evidence that this mechanism may apply to other forebrain synapses, where GluD1 is widely expressed.

Long-term potentiation (LTP) is a persistent strengthening of synaptic transmission in the brain and is arguably the most compelling cellular and molecular model for learning and memory. Previous work found that both AMPA receptors and exogenously expressed kainate receptors are equally capable of expressing LTP, despite their limited homology and their association with distinct auxiliary subunits, indicating that LTP is far more promiscuous than previously thought. What might these two subtypes of glutamate receptor have in common? Using a single-cell molecular replacement strategy, we demonstrate that the AMPA receptor auxiliary subunit TARP γ-8, via its PDZ-binding motif, is indispensable for both basal synaptic transmission and LTP. Remarkably, kainate receptors and their auxiliary subunits Neto proteins share the same requirement of PDZ-binding domains for synaptic trafficking and LTP. Together, these results suggest that a minimal postsynaptic requirement for LTP is the PDZ binding of glutamate receptors/auxiliary subunits to PSD scaffolding proteins.