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Expansion of the neocortex is thought to pave the way towards acquisition of higher cognitive functions in mammals. The highly conserved Notch signaling pathway plays a crucial role in this process by regulating the size of the cortical progenitor pool, in part by controlling the balance between self-renewal and differentiation. In this review, we introduce the components of Notch signaling pathway as well as the different mode of molecular mechanisms, including trans- and cis-regulatory processes. We focused on the recent findings with regard to the expression pattern and levels in regulating neocortical formation in mammals and its interactions with other known signaling pathways, including Slit-Robo signaling and Shh signaling. Finally, we review the functions of Notch signaling pathway in different species as well as other developmental process, mainly somitogenesis, to discuss how modifications to the Notch signaling pathway can drive the evolution of the neocortex.

In mammals, microRNAs can be actively secreted from cells to blood. miR‐29b‐3p has been shown to play a pivotal role in muscle atrophy, but its role in intercellular communication is largely unknown. Here, we showed that miR‐29b‐3p was upregulated in normal and premature aging mouse muscle and plasma. miR‐29b‐3p was also upregulated in the blood of aging individuals, and circulating levels of miR‐29b‐3p were negatively correlated with relative appendicular skeletal muscle. Consistently, miR‐29b‐3p was observed in exosomes isolated from long‐term differentiated atrophic C2C12 cells. When C2C12‐derived miR‐29b‐3p‐containing exosomes were uptaken by neuronal SH‐SY5Y cells, increased miR‐29b‐3p levels in recipient cells were observed. Moreover, miR‐29b‐3p overexpression led to downregulation of neuronal‐related genes and inhibition of neuronal differentiation. Interestingly, we identified HIF1α‐AS2 as a novel c‐FOS targeting lncRNA that is induced by miR‐29b‐3p through down‐modulation of c‐FOS and is required for miR‐29b‐3p‐mediated neuronal differentiation inhibition. Our results suggest that atrophy‐associated circulating miR‐29b‐3p may mediate distal communication between muscle cells and neurons. miR‐29b‐3p‐containing exosomes released from atrophied muscle can be transported via the circulation and transferred to neuronal cells. Increased miR‐29b‐3p levels in neuronal cells may lead to inhibition of neuronal differentiation.

Focal cortical dysplasia (FCD), a major cause of drug-resistant epilepsy, involves abnormal neuronal migration and cortical architecture, yet its molecular basis remains poorly defined. Here, we identify FOXJ3 pathogenic variants in patients with autosomal dominant focal epilepsy and FCD. In the developing mouse cortex, FOXJ3 declines sharply in neural progenitors after embryonic day 15.5. In utero electroporation-mediated Foxj3 knockdown in mouse brains impairs neuronal migration, disrupts cortical lamination, and alters neuronal specification, promoting upper-layer neuron production at the expense of deeper-layer neurons. ChIP-seq and scRNA-seq analyses identify Pten as a key FOXJ3 target. Notably, Pten overexpression rescues cortical defects caused by FOXJ3 deficiency. FCD-associated variant fails to upregulate Pten , leading to dysregulated mTOR signaling and enlarged neuronal soma, a hallmark of FCD. These findings suggest that mutations in FOXJ3 may cause epilepsy and FCD and define a transcriptional program that regulates the PTEN-mTOR pathway for neuronal specification and cortical lamination. Researchers identify FOXJ3 variants in focal epilepsy and cortical dysplasia and show that FOXJ3 regulates neuronal migration and cortical layer formation by controlling the PTEN–mTOR pathway; disruption of this process leads to abnormal brain development.

During brain development, the nucleus of migrating neurons follows the centrosome and translocates into the leading process. Defects in these migratory events, which affect neuronal migration, cause lissencephaly and other neurodevelopmental disorders. However, the mechanism of nuclear translocation remains elusive. Using whole exome sequencing (WES), we identified a novel nonsense BICD2 variant p.(Lys775Ter) (K775X) from a lissencephaly patient. Interestingly, most BICD2 missense variants have been associated with human spinal muscular atrophy (SMA) without obvious brain malformations. By in utero electroporation, we showed that BicD2 knockdown in mouse embryos inhibited neuronal migration. Surprisingly, we observed severe blockage of neuronal migration in cells overexpressing K775X but not in those expressing wild-type BicD2 or SMA-associated missense variants. The centrosome of the mutant was, on average, positioned farther away from the nucleus, indicating a failure in nuclear translocation without affecting the centrosome movement. Furthermore, BicD2 localized at the nuclear envelope (NE) through its interaction with NE protein Nesprin-2. K775X variant disrupted this interaction and further interrupted the NE recruitment of BicD2 and dynein. Remarkably, fusion of BicD2-K775X with NE-localizing domain KASH resumed neuronal migration. Our results underscore impaired nuclear translocation during neuronal migration as an important pathomechanism of lissencephaly.

Mutations in RAB18 , a member of small G protein, cause Warburg micro syndrome (WARBM), whose clinical features include vision impairment, postnatal microcephaly, and lower limb spasticity. Previously, our Rab18 −/− mice exhibited hind limb weakness and spasticity as well as signs of axonal degeneration in the spinal cord and lumbar spinal nerves. However, the cellular and molecular function of RAB18 and its roles in the pathogenesis of WARBM are still not fully understood. Using immunofluorescence staining and expression of Rab18 and organelle markers, we find that Rab18 associates with lysosomes and actively traffics along neurites in cultured neurons. Interestingly, Rab18 −/− neurons exhibit impaired lysosomal transport. Using autophagosome marker LC3-II, we show that Rab18 dysfunction leads to aberrant autophagy activities in neurons. Electron microscopy further reveals accumulation of lipofuscin-like granules in the dorsal root ganglion of Rab18 −/− mice. Surprisingly, Rab18 colocalizes, cofractionates, and coprecipitates with the lysosomal regulator Rab7, mutations of which cause Charcot-Marie-Tooth (CMT) neuropathy type 2B. Moreover, Rab7 is upregulated in Rab18-deficient neurons, suggesting a compensatory effect. Together, our results suggest that the functions of RAB18 and RAB7 in lysosomal and autophagic activities may constitute an overlapping mechanism underlying WARBM and CMT pathogenesis in the nervous system.

Blood flow and a hormone called ghrelin help new neurons travel to where they are meant to be in the brain of adult mice.Blood flow and a hormone called ghrelin help new neurons travel to where they are meant to be in the brain of adult mice.

The forced swim test (FST) is a commonly used model to predict antidepressant efficacy. Uncovering the genetic basis of the model may unravel the mechanism of antidepressant treatment. FVB/NJ (FVB) and C57BL/6J (B6) were first identified as the response and non-response strains to fluoxetine (a serotonin-specific reuptake inhibitor antidepressant) treatment in the mouse FST. Simple-interval (SIM) and composite-interval (CIM) mappings were applied to map the quantitative trait loci (QTLs) of the anti-immobility effect of fluoxetine in FST (FST(FLX)) in 865 male B6×FVB-F2 mice. The brain mRNA expressions of the gene with the maximum QTL-linkage signal for FST(FLX) after the FST were compared between B6 and FVB mice and also compared between fluoxetine and saline treatment. The association of the variants in the human homologue of the mouse FST(FLX)-QTL gene with major depressive disorder (MDD) and antidepressant response were investigated in 1080 human subjects (MDD/control = 582/498). One linkage signal for FST(FLX)-QTL was detected at an intronic SNP (rs6215396) of the mouse Zfp326 gene (maximal CIM-LOD = 9.36). The Zfp326 mRNA expression in the FVB thalamus was significantly down-regulated by fluoxetine in the FST, and the higher FVB-to-B6 Zfp326 mRNA expressions in the frontal cortex, striatum and hypothalamus diminished after fluoxetine treatment. Two coding-synonymous SNPs (rs2816881 and rs10922744) in the human homologue of Zfp326, ZNF326, were significantly associated with the 8-week antidepressant treatment response in the MDD patients (Bonferroni-corrected p = 0.004-0.028). The findings suggest the involvement of the Zfp326 and ZNF326 genes in antidepressant treatment response.

Notch signaling plays a pivotal role in regulating various developmental processes, particularly in controlling the timing of neuronal production within the developing neocortex. Central to this regulatory mechanism is the oscillatory pattern of Delta, which functions as a developmental clock modulator. Its deficiency profoundly impairs mammalian brain formation, highlighting its fundamental role in brain development. However, zebrafish carrying a mutation in the functional ortholog DeltaC (dlc) within their functional ortholog exhibit an intact forebrain structure, implying evolutionary variations in Notch signaling within the forebrain. In this study, we unveil the distinct yet analogous expression profiles of Delta and Her genes in the developing vertebrate forebrain. Specifically, for the first time, we detected the oscillatory expression of the Delta gene dlc in the developing zebrafish forebrain. Although this oscillatory pattern appeared irregular and was not pervasive among the progenitor population, attenuation of the dlc-involved Notch pathway using a γ-secretase inhibitor impaired neuronal differentiation in the developing zebrafish forebrain, revealing the indispensable role of the dlc-involved Notch pathway in regulating early zebrafish neurogenesis. Taken together, our results demonstrate the foundational prototype of dlc-involved Notch signaling in the developing zebrafish forebrains, upon which the intricate patterns of the mammalian neocortex may have been sculpted.

Intracellular endogenous fluorescent co-enzymes, reduced nicotinamide adenine dinucleotide (NADH) and flavin adenine dinucleotide (FAD), play a pivotal role in cellular metabolism; quantitative assessment of their presence in living cells can be exploited to monitor cellular energetics in Parkinson’s disease (PD), a neurodegenerative disorder. Here, we applied two-photon fluorescence lifetime imaging microscopy (2P-FLIM) to noninvasively measure the fluorescence lifetime components of NADH and FAD and their relative contributions in MPP + (1-methyl-4-phenylpyridinium) treated neuronal cells, derived from PC12 cells treated with nerve growth factor (NGF), to mimic PD conditions. A systematic FLIM data analysis showed a statistically significant (p < 0.001) decrease in the fluorescence lifetime of both free and protein-bound NADH, as well as free and protein-bound FAD in MPP + treated cells. On the relative contributions of the free and protein-bound NADH and FAD to the life time, however, both the free NADH contribution and the corresponding protein-bound FAD contribution increase significantly (p < 0.001) in MPP + treated cells, compared to control cells. These results, which indicate a shift in energy production in the MPP + treated cells from oxidative phosphorylation towards anaerobic glycolysis, can potentially be used as cellular metabolic metrics to assess the condition of PD at the cellular level.

Understanding the genetic causes of diseases that affect pancreatic β cells and neurons can give insights into pathways essential for both cell types. Microcephaly, epilepsy, and diabetes syndrome (MEDS) is a congenital disorder with two known etiological genes, IER3IP1 and YIPF5. Both genes encode proteins involved in endoplasmic reticulum (ER) to Golgi trafficking. We used genome sequencing to identify 6 individuals with MEDS caused by biallelic variants in the potentially novel disease gene TMEM167A. All had neonatal diabetes (diagnosed at <6 months) and severe microcephaly, and 5 also had epilepsy. TMEM167A is highly expressed in developing and adult human pancreas and brain. To gain insights into the mechanisms leading to diabetes, we silenced TMEM167A in EndoC-βH1 cells and knocked-in one patient's variant, p.Val59Glu, in induced pluripotent stem cells (iPSCs). Both TMEM167A depletion in EndoC-βH1 cells and the p.Val59Glu variant in iPSC-derived β cells sensitized β cells to ER stress. The p.Val59Glu variant impaired proinsulin trafficking to the Golgi and induced iPSC-β cell dysfunction. The discovery of TMEM167A variants as a genetic cause of MEDS highlights a critical role of TMEM167A in the ER to Golgi pathway in β cells and neurons.