Neural Progenitor Proliferation Research Articles

Effects of Moleac 901 after severe spinal cord injury on chronic phase in Wistar rats

BackgroundMLC901 is a phytopharmaceutical comprising significant compounds that can induce microenvironments conducive to the proliferation and specialization of neural cell progenitors. This study investigates the impact of administering MLC901, reducing the expression of NG2 and caspase-3 and increasing IL-10 levels, as well as histopathological and motor function, after severe spinal cord injury (SCI) in the chronic phase. MethodsThe study employed a randomized post-test-only control group design conducted between February and April 2023 at the Integrated Biomedical Laboratory. The participants in this study were categorized into three distinct groups: normal control, negative control, and therapy. A cohort of 18 rats was utilized for the study, with each group assigned a random allocation of six rats as subjects. ResultsThe findings demonstrated a statistically significant disparity in the average NG2 expression (−52.00 ± 20.03; p ≤ 0.05), as well as Caspase-3 expression (−94.89 ± 8.57; p ≤ 0.05), which exhibited a lower magnitude. The levels of IL-10 (8.96 ± 3.98; p ≤ 0.05) were observed to be higher, along with an elevation in BBB score (7.67 ± 0.89; p ≤ 0.05), which was more pronounced in the treatment group compared to the negative control group. The cut-off point for cavitation diameter is determined to be 114.915 μm, exhibiting a sensitivity and specificity of 100%. The area under curve (AUC) value is 1.0. The administration of MLC901 demonstrated a strong positive correlation with the increase in IL-10 levels (B 8.968; p ≤ 0.05), as well as a substantial negative correlation with the decrease in Caspase-3 expression (B −52.000; p ≤ 0.05) and NG2 expression (B −94.892; p ≤ 0.05). The administration of MLC901 via the upregulation of NG2 and Caspase-3 significantly increased the Basso, Beattie, and Bresnahan (BBB) scores. ConclusionsMLC901 positively affects motor and histopathological outcomes in the chronic phase of severe SCI in the Wistar rat model. These benefits are believed to be achieved by suppressing gliosis, neuroapoptosis, and neuroinflammation processes.

Defined co-cultures of glutamatergic and GABAergic neurons with a mutation in DISC1 reveal aberrant phenotypes in GABAergic neurons

BackgroundMutations in the gene DISC1 are associated with increased risk for schizophrenia, bipolar disorder and major depression. The study of mutated DISC1 represents a well-known and comprehensively characterized approach to understand neuropsychiatric disease mechanisms. However, previous studies have mainly used animal models or rather heterogeneous populations of iPSC-derived neurons, generated by undirected differentiation, to study the effects of DISC1 disruption. Since major hypotheses to explain neurodevelopmental, psychiatric disorders rely on altered neuronal connectivity observed in patients, an ideal iPSC-based model requires accurate representation of the structure and complexity of neuronal circuitries. In this study, we made use of an isogenic cell line with a mutation in DISC1 to study neuronal synaptic phenotypes in a culture system comprising a defined ratio of NGN2 and ASCL1/DLX2 (AD2)-transduced neurons, enriched for glutamatergic and GABAergic neurons, respectively, to mimic properties of the cortical microcircuitry.ResultsIn heterozygous DISC1 mutant neurons, we replicated the expected phenotypes including altered neural progenitor proliferation as well as neurite outgrowth, deregulated DISC1-associated signaling pathways, and reduced synaptic densities in cultures composed of glutamatergic neurons. Cultures comprising a defined ratio of NGN2 and AD2 neurons then revealed considerably increased GABAergic synapse densities, which have not been observed in any iPSC-derived model so far. Increased inhibitory synapse densities could be associated with an increased efficiency of GABAergic differentiation, which we observed in AD2-transduced cultures of mutant neurons. Additionally, we found increased neuronal activity in GABAergic neurons through calcium imaging while the activity pattern of glutamatergic neurons remained unchanged.ConclusionsIn conclusion, our results demonstrate phenotypic differences in a co-culture comprising a defined ratio of DISC1 mutant NGN2 and AD2 neurons, as compared to culture models comprising only one neuronal cell type. Altered synapse numbers and neuronal activity imply that DISC1 impacts the excitatory/inhibitory balance in NGN2/AD2 co-cultures, mainly through increased GABAergic input.

Hedgehog Signaling in Cortical Development.

The Hedgehog (Hh) pathway plays a crucial role in embryonic development, acting both as a morphogenic signal that organizes tissue formation and a potent mitogenic signal driving cell proliferation. Dysregulated Hh signaling leads to various developmental defects in the brain. This article aims to review the roles of Hh signaling in the development of the neocortex in the mammalian brain, focusing on its regulation of neural progenitor proliferation and neuronal production. The review will summarize studies on genetic mouse models that have targeted different components of the Hh pathway, such as the ligand Shh, the receptor Ptch1, the GPCR-like transducer Smo, the intracellular transducer Sufu, and the three Gli transcription factors. As key insights into the Hh signaling transduction mechanism were obtained from mouse models displaying neural tube defects, this review will also cover some studies on Hh signaling in neural tube development. The results from these genetic mouse models suggest an intriguing hypothesis that elevated Hh signaling may play a role in the gyrification of the brain in certain species. Additionally, the distinctive production of GABAergic interneurons in the dorsal cortex in the human brain may also be linked to the extension of Hh signaling from the ventral to the dorsal brain region. Overall, these results suggest key roles of Hh signaling as both a morphogenic and mitogenic signal during the forebrain development and imply the potential involvement of Hh signaling in the evolutionary expansion of the neocortex.

GTF2I dosage regulates neuronal differentiation and social behavior in 7q11.23 neurodevelopmental disorders.

Copy number variations at 7q11.23 cause neurodevelopmental disorders with shared and opposite manifestations. Deletion causes Williams-Beuren syndrome featuring hypersociability, while duplication causes 7q11.23 microduplication syndrome (7Dup), frequently exhibiting autism spectrum disorder (ASD). Converging evidence indicates GTF2I as key mediator of the cognitive-behavioral phenotypes, yet its role in cortical development and behavioral hallmarks remains largely unknown. We integrated proteomic and transcriptomic profiling of patient-derived cortical organoids, including longitudinally at single-cell resolution, to dissect 7q11.23 dosage-dependent and GTF2I-specific disease mechanisms. We observed dosage-dependent impaired dynamics of neural progenitor proliferation, transcriptional imbalances, and highly specific alterations in neuronal output, leading to precocious excitatory neuron production in 7Dup, which was rescued by restoring physiological GTF2I levels. Transgenic mice with Gtf2i duplication recapitulated progenitor proliferation and neuronal differentiation defects alongside ASD-like behaviors. Consistently, inhibition of lysine demethylase 1 (LSD1), a GTF2I effector, was sufficient to rescue ASD-like phenotypes in transgenic mice, establishing GTF2I-LSD1 axis as a molecular pathway amenable to therapeutic intervention in ASD.

Neocortical neuronal production and maturation defects in the TcMAC21 mouse model of Down syndrome

Down syndrome (DS) results from trisomy of human chromosome 21 (HSA21), and DS research has been conducted by the use of mouse models. We previously generated a humanized mouse model of DS, TcMAC21, which carries the long arm of HSA21. These mice exhibit learning and memory deficits, and may reproduce neurodevelopmental alterations observed in humans with DS. Here, we performed histologic studies of the TcMAC21 forebrain from embryonic to adult stages. The TcMAC21 neocortex showed reduced proliferation of neural progenitors and delayed neurogenesis. These abnormalities were associated with a smaller number of projection neurons and interneurons. Further, (phospho-)proteomic analysis of adult TcMAC21 cortex revealed alterations in the phosphorylation levels of a series of synaptic proteins. The TcMAC21 mouse model shows similar brain development abnormalities as DS, and will be a valuable model to investigate prenatal and postnatal causes of intellectual disability in humans with DS.

Modeling early human cortical development and evaluating neurotoxicity with a forebrain organoid system

The complexity and subtlety of brain development renders it challenging to examine effects of environmental toxicants on human fetal brain development. Advances in pluripotent cell-derived organoid systems open up novel avenues for human development, disease and toxicity modeling. Here, we have established a forebrain organoid system and recapitulated early human cortical development spatiotemporally including neuroepithelium induction, apical-basal axis formation, neural progenitor proliferation and maintenance, neuronal differentiation and layer/region patterning. To explore whether this forebrain organoid system is suitable for neurotoxicity modeling, we subjected the organoids to bisphenol A (BPA), a common environmental toxicant of global presence and high epidemic significance. BPA exposure caused substantial abnormalities in key cortical developmental events, inhibited progenitor cell proliferation and promoted precocious neuronal differentiation, leading premature progenitor cell depletion and aberrant cortical layer patterning and structural organization. Consistent with an antagonistic mechanism between thyroid hormone and BPA, T3 supplementation attenuated BPA-mediated cortical developmental abnormalities. Altogether, our in vitro recapitulation of cortical development with forebrain organoids provides a paradigm for efficient neural development and toxicity modeling and related remedy testing/screening.

Dbx2, an Aging-Related Homeobox Gene, Inhibits the Proliferation of Adult Neural Progenitors

In the adult mouse brain, the subventricular zone (SVZ) underlying the lateral ventricles harbours a population of quiescent neural stem cells, which can be activated (aNSCs) to initiate proliferation and generate a neurogenic lineage consisting of transit amplifying progenitors (TAPs), neuroblasts (NBs) and newborn neurons. This process is markedly reduced during aging. Recent studies suggest that the aged SVZ niche decreases the pool of proliferating neural/stem progenitor cells (NSPCs), and hence adult neurogenesis, by causing transcriptomic changes that promote NSC quiescence. The transcription factors that mediate these changes, however, remain unclear. We previously found that the homeobox gene Dbx2 is upregulated in NSPCs of the aged mouse SVZ and can inhibit the growth of NSPC cultures. Here, we further investigate its role as a candidate transcriptional regulator of neurogenic decline. We show that Dbx2 expression is downregulated by Epidermal Growth Factor receptor signaling, which promotes NSPC proliferation and decreases in the aged SVZ. By means of transgenic NSPC lines overexpressing Dbx2, we also show that this gene inhibits NSPC proliferation by hindering the G2/M transition. Furthermore, we exploit RNA sequencing of transgenic NSPCs to elucidate the transcriptomic networks modulated by Dbx2. Among the top hits, we report the downregulation of the molecular pathways implicated in cell cycle progression. Accordingly, we find that Dbx2 function is negatively correlated with the transcriptional signatures of proliferative NSPCs (aNSCs, TAPs and early NBs). These results point to Dbx2 as a transcription factor relaying the anti-neurogenic input of the aged niche to the NSPC transcriptome.Graphical

Ret deficiency decreases neural crest progenitor proliferation and restricts fate potential during enteric nervous system development

The receptor tyrosine kinase RET plays a critical role in the fate specification of enteric neural crest-derived cells (ENCDCs) during enteric nervous system (ENS) development. RET loss of function (LoF) is associated with Hirschsprung disease (HSCR), which is marked by aganglionosis of the gastrointestinal (GI) tract. Although the major phenotypic consequences and the underlying transcriptional changes from Ret LoF in the developing ENS have been described, cell type- and state-specific effects are unknown. We performed single-cell RNA sequencing on an enriched population of ENCDCs from the developing GI tract of Ret null heterozygous and homozygous mice at embryonic day (E)12.5 and E14.5. We demonstrate four significant findings: 1) Ret-expressing ENCDCs are a heterogeneous population comprising ENS progenitors as well as glial- and neuronal-committed cells; 2) neurons committed to a predominantly inhibitory motor neuron developmental trajectory are not produced under Ret LoF, leaving behind a mostly excitatory motor neuron developmental program; 3) expression patterns of HSCR-associated and Ret gene regulatory network genes are impacted by Ret LoF; and 4) Ret deficiency leads to precocious differentiation and reduction in the number of proliferating ENS precursors. Our results support a model in which Ret contributes to multiple distinct cellular phenotypes during development of the ENS, including the specification of inhibitory neuron subtypes, cell cycle dynamics of ENS progenitors, and the developmental timing of neuronal and glial commitment.

SWI/SNF complexes are required for retinal pigmented epithelium differentiation and for the inhibition of cell proliferation and neural differentiation programs.

During embryonic development, tissue-specific transcription factors and chromatin remodelers function together to ensure gradual, coordinated differentiation of multiple lineages. Here, we define this regulatory interplay in the developing retinal pigmented epithelium (RPE), a neuroectodermal lineage essential for the development, function and maintenance of the adjacent retina. We present a high-resolution spatial transcriptomic atlas of the developing mouse RPE and the adjacent ocular mesenchyme obtained by geographical position sequencing (Geo-seq) of a single developmental stage of the eye that encompasses young and more mature ocular progenitors. These transcriptomic data, available online, reveal the key transcription factors and their gene regulatory networks during RPE and ocular mesenchyme differentiation. Moreover, conditional inactivation followed by Geo-seq revealed that this differentiation program is dependent on the activity of SWI/SNF complexes, shown here to control the expression and activity of RPE transcription factors and, at the same time, inhibit neural progenitor and cell proliferation genes. The findings reveal the roles of the SWI/SNF complexes in controlling the intersection between RPE and neural cell fates and the coupling of cell-cycle exit and differentiation.

Brain-specific Pd1 deficiency leads to cortical neurogenesis defects and depressive-like behaviors in mice.

Embryonic neurogenesis is tightly regulated by multiple factors to ensure the precise development of the cortex. Deficiency in neurogenesis may result in behavioral abnormalities. Pd1 is a well-known inhibitory immune molecule, but its function in brain development remains unknown. Here, we find brain specific deletion of Pd1 results in abnormal cortical neurogenesis, including enhanced proliferation of neural progenitors and reduced neuronal differentiation. In addition, neurons in Pd1 knockout mice exhibit abnormal morphology, both the total length and the number of primary dendrites were reduced. Moreover, Pd1cKO mice exhibit depressive-like behaviors, including immobility, despair, and anhedonia. Mechanistically, Pd1 regulates embryonic neurogenesis by targeting Pax3 through the β-catenin signaling pathway. The constitutive expression of Pax3 partly rescues the deficiency of neurogenesis in the Pd1 deleted embryonic brain. Besides, the administration of β-catenin inhibitor, XAV939, not only rescues abnormal brain development but also ameliorates depressive-like behaviors in Pd1cKO mice. Simultaneously, Pd1 plays a similar role in human neural progenitor cells (hNPCs) proliferation and differentiation. Taken together, our findings reveal the critical role and regulatory mechanism of Pd1 in embryonic neurogenesis and behavioral modulation, which could contribute to understanding immune molecules in brain development.

Transcriptional control of embryonic and adult neural progenitor activity.

Neural precursors generate neurons in the embryonic brain and in restricted niches of the adult brain in a process called neurogenesis. The precise control of cell proliferation and differentiation in time and space required for neurogenesis depends on sophisticated orchestration of gene transcription in neural precursor cells. Much progress has been made in understanding the transcriptional regulation of neurogenesis, which relies on dose- and context-dependent expression of specific transcription factors that regulate the maintenance and proliferation of neural progenitors, followed by their differentiation into lineage-specified cells. Here, we review some of the most widely studied neurogenic transcription factors in the embryonic cortex and neurogenic niches in the adult brain. We compare functions of these transcription factors in embryonic and adult neurogenesis, highlighting biochemical, developmental, and cell biological properties. Our goal is to present an overview of transcriptional regulation underlying neurogenesis in the developing cerebral cortex and in the adult brain.

A complex relation between levels of adult hippocampal neurogenesis and expression of the immature neuron marker doublecortin.

We investigated the mechanisms underlying the effects of the antidepressant fluoxetine on behavior and adult hippocampal neurogenesis (AHN). After confirming our earlier report that the signaling molecule β-arrestin-2 (β-Arr2) is required for the antidepressant-like effects of fluoxetine, we found that the effects of fluoxetine on proliferation of neural progenitors and survival of adult-born granule cells are absent in the β-Arr2 knockout (KO) mice. To our surprise, fluoxetine induced a dramatic upregulation of the number of doublecortin (DCX)-expressing cells in the β-Arr2 KO mice, indicating that this marker can be increased even though AHN is not. We discovered two other conditions where a complex relationship occurs between the number of DCX-expressing cells compared to levels of AHN: a chronic antidepressant model where DCX is upregulated and an inflammation model where DCX is downregulated. We concluded that assessing the number of DCX-expressing cells alone to quantify levels of AHN can be complex and that caution should be applied when label retention techniques are unavailable.

Ccdc85c-Par3 condensates couple cell polarity with Notch to control neural progenitor proliferation

Polarity proteins regulate the proliferation and differentiation of neural progenitors to generate neurons during brain development through multiple signaling pathways. However, how cell polarity couples the signaling pathways remains unclear. Here, we show that coiled-coil domain-containing protein 85c (Ccdc85c) interacts with the polarity protein Par3 to regulate the proliferation of radial glial cells (RGCs) via phase separation coupled to percolation (PSCP). We find that the interaction with Ccdc85c relieves the intramolecular auto-inhibitionof Par3, which leads to PSCP of Par3. Downregulation of Ccdc85c causes RGC differentiation. Importantly, the open conformation of Par3 facilitates the recruitment of the Notch regulator Numb to the Par3 condensates, which might prevent the attenuation of Notch activity to maintain RGC proliferation. Furthermore, ectopic activation of Notch signaling rescues RGC proliferation defects caused by the downregulation of Ccdc85c. These results suggest that Ccdc85c-mediated PSCP of Par3 regulates Notch signaling to control RGC proliferation during brain development.

Single-cell RNA-sequencing analysis reveals enhanced non-canonical neurotrophic factor signaling in the subacute phase of traumatic brain injury.

Traumatic brain injury (TBI) is a leading cause of long-term disability in young adults and induces complex neuropathological processes. Cellular autonomous and intercellular changes during the subacute phase contribute substantially to the neuropathology of TBI. However, the underlying mechanisms remain elusive. In this study, we explored the dysregulated cellular signaling during the subacute phase of TBI. Single-cell RNA-sequencing data (GSE160763) of TBI were analyzed to explore the cell-cell communication in the subacute phase of TBI. Upregulated neurotrophic factor signaling was validated in a mouse model of TBI. Primary cell cultures and cell lines were used as in vitro models to examine the potential mechanisms affecting signaling. Single-cell RNA-sequencing analysis revealed that microglia and astrocytes were the most affected cells during the subacute phase of TBI. Cell-cell communication analysis demonstrated that signaling mediated by the non-canonical neurotrophic factors midkine (MDK), pleiotrophin (PTN), and prosaposin (PSAP) in the microglia/astrocytes was upregulated in the subacute phase of TBI. Time-course profiling showed that MDK, PTN, and PSAP expression was primarily upregulated in the subacute phase of TBI, and astrocytes were the major source of MDK and PTN after TBI. In vitro studies revealed that the expression of MDK, PTN, and PSAP in astrocytes was enhanced by activated microglia. Moreover, MDK and PTN promoted the proliferation of neural progenitors derived from human-induced pluripotent stem cells (iPSCs) and neurite growth in iPSC-derived neurons, whereas PSAP exclusively stimulated neurite growth. The non-canonical neurotrophic factors MDK, PTN, and PSAP were upregulated in the subacute phase of TBI and played a crucial role in neuroregeneration.

Bacterial TLR2/6 Ligands Block Ciliogenesis, Derepress Hedgehog Signaling, and Expand the Neocortex.

Microbial components have a range of direct effects on the fetal brain. However, little is known about the cellular targets and molecular mechanisms that mediate these effects. Neural progenitor cells (NPCs) control the size and architecture of the brain and understanding the mechanisms regulating NPCs is crucial to understanding brain developmental disorders. We identify ventricular radial glia (vRG), the primary NPC, as the target of bacterial cell wall (BCW) generated during the antibiotic treatment of maternal pneumonia. BCW enhanced proliferative potential of vRGs by shortening the cell cycle and increasing self-renewal. Expanded vRGs propagated to increase neuronal output in all cortical layers. Remarkably, Toll-like receptor 2 (TLR2), which recognizes BCW, localized at the base of primary cilia in vRGs and the BCW-TLR2 interaction suppressed ciliogenesis leading to derepression of Hedgehog (HH) signaling and expansion of vRGs. We also show that TLR6 is an essential partner of TLR2 in this process. Surprisingly, TLR6 alone was required to set the number of cortical neurons under healthy conditions. These findings suggest that an endogenous signal from TLRs suppresses cortical expansion during normal development of the neocortex and that BCW antagonizes that signal through the TLR2/cilia/HH signaling axis changing brain structure and function. IMPORTANCE Fetal brain development in early gestation can be impacted by transplacental infection, altered metabolites from the maternal microbiome, or maternal immune activation. It is less well understood how maternal microbial subcomponents that cross the placenta, such as bacterial cell wall (BCW), directly interact with fetal neural progenitors and neurons and affect development. This scenario plays out in the clinic when BCW debris released during antibiotic therapy of maternal infection traffics to the fetal brain. This study identifies the direct interaction of BCW with TLR2/6 present on the primary cilium, the signaling hub on fetal neural progenitor cells (NPCs). NPCs control the size and architecture of the brain and understanding the mechanisms regulating NPCs is crucial to understanding brain developmental disorders. Within a window of vulnerability before the appearance of fetal immune cells, the BCW-TLR2/6 interaction results in the inhibition of ciliogenesis, derepression of Sonic Hedgehog signaling, excess proliferation of neural progenitors, and abnormal cortical architecture. In the first example of TLR signaling linked to Sonic Hedgehog, BCW/TLR2/6 appears to act during fetal brain morphogenesis to play a role in setting the total cell number in the neocortex.

Homophilic interaction of cell adhesion molecule 3 coordinates retina neuroepithelial cell proliferation.

Correct cell number generation is central to tissue development. However, in vivo roles of coordinated proliferation of individual neural progenitors in regulating cell numbers of developing neural tissues and the underlying molecular mechanism remain mostly elusive. Here, we showed that wild-type (WT) donor retinal progenitor cells (RPCs) generated significantly expanded clones in host retinae with G1-lengthening by p15 (cdkn2a/b) overexpression (p15+) in zebrafish. Further analysis showed that cell adhesion molecule 3 (cadm3) was reduced in p15+ host retinae, and overexpression of either full-length or ectodomains of Cadm3 in p15+ host retinae markedly suppressed the clonal expansion of WT donor RPCs. Notably, WT donor RPCs in retinae with cadm3 disruption recapitulated expanded clones that were found in p15+ retinae. More strikingly, overexpression of Cadm3 without extracellular ig1 domain in RPCs resulted in expanded clones and increased retinal total cell number. Thus, homophilic interaction of Cadm3 provides an intercellular mechanism underlying coordinated cell proliferation to ensure cell number homeostasis of the developing neuroepithelia.

Regulatory and coding sequences of TRNP1 co-evolve with brain size and cortical folding in mammals.

Brain size and cortical folding have increased and decreased recurrently during mammalian evolution. Identifying genetic elements whose sequence or functional properties co-evolve with these traits can provide unique information on evolutionary and developmental mechanisms. A good candidate for such a comparative approach is TRNP1, as it controls proliferation of neural progenitors in mice and ferrets. Here, we investigate the contribution of both regulatory and coding sequences of TRNP1 to brain size and cortical folding in over 30 mammals. We find that the rate of TRNP1 protein evolution (ω) significantly correlates with brain size, slightly less with cortical folding and much less with body size. This brain correlation is stronger than for >95% of random control proteins. This co-evolution is likely affecting TRNP1 activity, as we find that TRNP1 from species with larger brains and more cortical folding induce higher proliferation rates in neural stem cells. Furthermore, we compare the activity of putative cis-regulatory elements (CREs) of TRNP1 in a massively parallel reporter assay and identify one CRE that likely co-evolves with cortical folding in Old World monkeys and apes. Our analyses indicate that coding and regulatory changes that increased TRNP1 activity were positively selected either as a cause or a consequence of increases in brain size and cortical folding. They also provide an example how phylogenetic approaches can inform biological mechanisms, especially when combined with molecular phenotypes across several species.

Hippocampal Noradrenaline Is a Positive Regulator of Spatial Working Memory and Neurogenesis in the Rat

Loss of noradrenaline (NA)-rich afferents from the Locus Coeruleus (LC) ascending to the hippocampal formation has been reported to dramatically affect distinct aspects of cognitive function, in addition to reducing the proliferation of neural progenitors in the dentate gyrus. Here, the hypothesis that reinstating hippocampal noradrenergic neurotransmission with transplanted LC-derived neuroblasts would concurrently normalize both cognitive performance and adult hippocampal neurogenesis was investigated. Post-natal day (PD) 4 rats underwent selective immunolesioning of hippocampal noradrenergic afferents followed, 4 days later, by the bilateral intrahippocampal implantation of LC noradrenergic-rich or control cerebellar (CBL) neuroblasts. Starting from 4 weeks and up to about 9 months post-surgery, sensory-motor and spatial navigation abilities were evaluated, followed by post-mortem semiquantitative tissue analyses. All animals in the Control, Lesion, Noradrenergic Transplant and Control CBL Transplant groups exhibited normal sensory-motor function and were equally efficient in the reference memory version of the water maze task. By contrast, working memory abilities were seen to be consistently impaired in the Lesion-only and Control CBL-Transplanted rats, which also exhibited a virtually complete noradrenergic fiber depletion and a significant 62-65% reduction in proliferating 5-bromo-2'deoxyuridine (BrdU)-positive progenitors in the dentate gyrus. Notably, the noradrenergic reinnervation promoted by the grafted LC, but not cerebellar neuroblasts, significantly ameliorated working memory performance and reinstated a fairly normal density of proliferating progenitors. Thus, LC-derived noradrenergic inputs may act as positive regulators of hippocampus-dependent spatial working memory possibly via the concurrent maintenance of normal progenitor proliferation in the dentate gyrus.

Dopey2 and Pcdh7 orchestrate the development of embryonic neural stem cells/ progenitors in zebrafish.

DOPEY2 has been shown to be associated with Down syndrome and PCDH7 might be involved in Rett syndrome and MECP2 duplication syndrome. The mechanism how both proteins play roles in these syndromes are largely unknown. Here, we show that Dopey2 and Pcdh7 balance the proliferation and differentiation of neural stem cells and progenitors during embryonic neurogenesis to generate proper size and architecture of zebrafish brains. Dopey2 and Pcdh7 mutually restricted expression of each other in zebrafish embryos. Dopey2 was responsible for the proliferation of neural stem cells/progenitors, whereas Pcdh7 was responsible for the differentiation of neural stem cells/progenitors. Both proteins were shown to orchestrate the proper development and arrangement of neural cells in zebrafish embryonic brains. The results provide an insight into mechanisms to understand how the embryonic brain is constituted and how developmental defects occur in the brains of patients with Down syndrome, Rett syndrome, or MECP2 duplication syndrome.

The role of PQBP1 in neural development and function.

Mutations in the polyglutamine tract-binding protein 1 (PQBP1) gene are associated with Renpenning syndrome, which is characterized by microcephaly, intellectual deficiency, short stature, small testes, and distinct facial dysmorphism. Studies using different models have revealed that PQBP1 plays essential roles in neural development and function. In this mini-review, we summarize recent findings relating to the roles of PQBP1 in these processes, including in the regulation of neural progenitor proliferation, neural projection, synaptic growth, neuronal survival, and cognitive function via mRNA transcription and splicing-dependent or -independent processes. The novel findings provide insights into the mechanisms underlying the pathogenesis of Renpenning syndrome and may advance drug discovery and treatment for this condition.