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Neuronal migration is essential for constructing functional neural networks. Two posterior septal (PS) nuclei, the triangular septal nucleus and bed nuclei of the anterior commissure, are involved in fear and anxiety. During development, glutamatergic PS neurons undergo long-distance rostrodorsal migration from the thalamic eminence (TE) of the diencephalon, then settle in the caudalmost telencephalon. However, the developmental behavior of PS neurons and the guidance structures facilitating their migration remain unknown. We previously demonstrated the migration of PS neurons along the fornix, a major efferent pathway from the hippocampal formation. Here, we show that the postcommissural fornix is essential for PS neuron migration which is largely confined to its axonal tract, which grows in the opposite direction as PS neuron migration. Fornical axons reach the TE prior to initiation of PS neuron rostrodorsal migration. Ectopic expression of Semaphorin 3 A in the dorsomedial cortex resulted in defective fornix formation. Furthermore, loss of the postcommissural fornix stalled PS neuron migration resulting in abnormal accumulation near their origin. This suggests that PS neurons utilize the postcommissural fornix as a permissive corridor during migration beyond the diencephalic-telencephalic boundary. This axonal support is essential for the functional organization of the heterogeneous septal nuclear complex.

Background: Thiel cadavers have been reported to have lifelike flexibility and mechanical properties, but whether they are useful for measurement of the ulnohumeral joint space (JS) is unclear. The contributions of the third and fourth digits and the second and fifth digits of the flexor digitorum superficialis (FDS) to elbow valgus stability are also unknown. Purpose: To (1) clarify whether Thiel cadavers can be used for JS measurement on ultrasound and (2) identify the contributions to valgus stability of the third and fourth digits and the second and fifth digits of the FDS. Study Design: Descriptive laboratory study. Methods: In experiment 1 (12 elbows from human volunteers and 12 elbows from Thiel cadavers), valgus stress was increased gradually from 0 to 30 to 60 N, and the JS was compared on ultrasound between groups at each load. In experiment 2 (13 elbows from Thiel cadavers), specimens were divided into 2 groups, and the JS was measured for group 1 with the FDS intact, with tendinous insertions of the third and fourth digits cut (3/4-cut state), and with tendinous insertions of all fingers cut (all-cut state); and for group 2 at intact FDS, with tendinous insertions of the second and fifth digits cut (2/5-cut state), and at all-cut. Results: In experiment 1, the rate of change of the JS increased significantly with elbow valgus stress in both humans and Thiel cadavers, with no significant difference between groups. In experiment 2, the JS was significantly greater in the 3/4- and 2/5-cut states compared with the intact state at both 30 N (Δ3/4-cut vs intact = 0.23 mm [P = .01]; Δ2/5-cut vs intact = 0.32 mm [P = .02]) and 60 N (Δ3/4-cut vs intact = 0.33 mm [P = .002]; Δ2/5-cut vs intact = 0.37 mm [P = .04]). There was no significant difference in JS measurements between the 3/4- and 2/5-cut states at any load. Conclusion: Thiel cadavers showed JS changes similar to those of humans when valgus stress was applied. The third and fourth digits and the second and fifth digits of the FDS were involved in valgus stability, and there was no difference in their respective contributions. Clinical Relevance: This study may help in identifying function of the FDS based on structure.

This study aimed to clarify the differences in the stabilizing functions of the upper and lower fiber bundles of the anterior talofibular ligament (ATFL). Five Thiel-fixed cadavers (10 ft) were divided into an upper fiber bundle cut group (upper-cut group, 5 ft) and a lower fiber bundle cut group (lower-cut group, 5 ft). The angular conditions were set as 0-degree ankle dorsiflexion, 15-degree plantar flexion, and 30-degree plantar flexion. Anterior drawer and inversion stresses were applied using a Telos stress device at 120 N. Measurements were obtained when the upper and lower fiber bundles of the ATFL were intact (intact condition) and when either the upper or lower fiber bundle was severed (cut condition). For each group, the distance between the lateral malleolus and talus was measured using an ultrasound diagnostic device under both the intact and cut conditions and compared. Regarding anterior drawer stress, the displacement rate (%) significantly increased in both the upper- and lower-cut groups under the cut condition at 30-degree plantar flexion. Meanwhile, for the inversion stress, only the upper-cut group demonstrated a significantly increased displacement rate (%) under the cut condition at 0-degree dorsiflexion. No significant difference in either anterior drawer stress or inversion stress at any angle was observed between the two groups. Both the upper and lower fiber bundles of the ATFL may be involved in stabilizing ankle function during anterior drawer stress at 30-degree plantar flexion. In addition, the lower fiber bundle may play a role in stabilizing the ankle during inversion stress at 0-degree dorsiflexion.

The brain of the hagfish, a cyclostome related to the lamprey, develops domains equivalent to the median ganglionic eminence and the rhombic lip, resembling the brains of gnathostomes (jawed vertebrates), suggesting that brain regionalization in jawed vertebrates occurred before the divergence of cyclostomes and gnathostomes more than 500 million years ago. The early vertebrate brain revisited The brains of vertebrates are much more complex than those of their immediate invertebrate relations — tunicates and the amphioxus — raising questions about the origins and development of the brain. The jawless lamprey, an ancient vertebrate, was also thought to have a primitive 'ancestral' brain. In particular, the embryonic lamprey was thought to have characteristics resembling those of mutant mice lacking a structure called the medial ganglionic eminence (MGE). Shigeru Kuratani and colleagues now show that the hagfish, a close relative of the lamprey, develops domains equivalent to the MGE and also the rhombic lip, resembling the brains of jawed vertebrates (gnathostomes). A closer look at lampreys reveals that they too have similar structures. These findings suggest that brain regionalization as seen in jawed vertebrates dates back to the latest vertebrate ancestor prior to the divergence of cyclostomes and gnathostomes more than 500 million years ago. The vertebrate brain is highly complex, but its evolutionary origin remains elusive. Because of the absence of certain developmental domains generally marked by the expression of regulatory genes, the embryonic brain of the lamprey, a jawless vertebrate, had been regarded as representing a less complex, ancestral state of the vertebrate brain. Specifically, the absence of a Hedgehog- and Nkx2.1 -positive domain in the lamprey subpallium was thought to be similar to mouse mutants in which the suppression of Nkx2-1 leads to a loss of the medial ganglionic eminence 1 , 2 . Here we show that the brain of the inshore hagfish ( Eptatretus burgeri ), another cyclostome group, develops domains equivalent to the medial ganglionic eminence and rhombic lip, resembling the gnathostome brain. Moreover, further investigation of lamprey larvae revealed that these domains are also present, ruling out the possibility of convergent evolution between hagfish and gnathostomes. Thus, brain regionalization as seen in crown gnathostomes is not an evolutionary innovation of this group, but dates back to the latest vertebrate ancestor before the divergence of cyclostomes and gnathostomes more than 500 million years ago.

Human and mouse embryonic stem cells (HESCs and MESCs, respectively) self-renew indefinitely while maintaining the ability to generate all three germ-layer derivatives. Despite the importance of ESCs in developmental biology and their potential impact on tissue replacement therapy, the molecular mechanism underlying ESC self-renewal is poorly understood. Here we show that activation of the canonical Wnt pathway is sufficient to maintain self-renewal of both HESCs and MESCs. Although Stat-3 signaling is involved in MESC self-renewal, stimulation of this pathway does not support self-renewal of HESCs. Instead we find that Wnt pathway activation by 6-bromoindirubin-3′-oxime (BIO), a specific pharmacological inhibitor of glycogen synthase kinase-3 (GSK-3), maintains the undifferentiated phenotype in both types of ESCs and sustains expression of the pluripotent state-specific transcription factors Oct-3/4, Rex-1 and Nanog. Wnt signaling is endogenously activated in undifferentiated MESCs and is downregulated upon differentiation. In addition, BIO-mediated Wnt activation is functionally reversible, as withdrawal of the compound leads to normal multidifferentiation programs in both HESCs and MESCs. These results suggest that the use of GSK-3-specific inhibitors such as BIO may have practical applications in regenerative medicine.

The endoplasmic reticulum (ER), including the nuclear envelope, is a continuous and intricate membrane-bound organelle responsible for various cellular functions. In neurons, the ER network is found in cell bodies, axons, and dendrites. Recent studies indicate the involvement of the ER network in neuronal development, such as neuronal migration and axonal outgrowth. However, the regulation of neural development by ER-localized proteins is not fully understood. We previously reported that the multi-transmembrane protein Dpy19L1 is required for neuronal migration in the developing mouse cerebral cortex. A Dpy19L family member, Dpy19L2, which is a causative gene for human Globozoospermia, is suggested to act as an anchor of the acrosome to the nuclear envelope. In this study, we found that the patterns of exogenous Dpy19L1 were partially coincident with the ER, including the nuclear envelope in COS-7 cells at the level of the light microscope. The reticular distribution of Dpy19L1 was disrupted by microtubule depolymerization that induces retraction of the ER. Furthermore, Dpy19L1 showed a similar distribution pattern with a ER marker protein in embryonic mouse cortical neurons. Finally, we showed that Dpy19L1 knockdown mediated by siRNA resulted in decreased neurite outgrowth in cultured neurons. These results indicate that transmembrane protein Dpy19L1 is localized to the ER membrane and regulates neurite extension during development.

Septal nuclei are telencephalic structures associated with a variety of brain functions as part of the limbic system. The two posterior septal nuclei, the triangular septal nucleus (TS) and the bed nuclei of the anterior commissure (BAC), are involved in fear and anxiety through their projections to the medial habenular nucleus. However, the development of both the TS and BAC remains unclear. Here, we found a novel caudal origin and putative migratory stream of mouse posterior septal neurons arising from the thalamic eminence (TE), a transient developmental structure at the rostral end of the rodent diencephalon. TE-derived cells, which have glutamatergic identity, migrated rostrally and entered the telencephalic territory by passing beneath the third ventricle. Subsequently, they turned dorsally toward the posterior septum. We also observed that TS and BAC neurons in the postnatal septum were labeled with GFP by in utero electroporation into the TE, suggesting a shared origin. Furthermore, TE-derived septal neurons migrated along the fornix, an efferent pathway from the hippocampus. These results demonstrate that posterior septal neurons have a distinct extratelencephalic origin from other septal nuclei. This heterogeneous origin may contribute to neuronal diversity of the septal nuclear complex.

Due to its long history, the study of human gross anatomy has not adequately incorporated modern embryological findings; consequently, the current understanding has often been incompatible with recent discoveries from molecular studies. Notably, the traditional epaxial and hypaxial muscle distinction, and their corresponding innervation by the dorsal and ventral rami of the spinal nerve, do not correspond to the primaxial and abaxial muscle distinction, defined by the mesodermal lineages of target tissues. To resolve the disagreement between adult anatomy and embryology, we here propose a novel hypothetical model of spinal nerve ramification. Our model is based on the previously unknown developmental process of the intercostal nerves. Observations of these nerves in the mouse embryos revealed that the intercostal nerves initially had superficial and deep ventral branches, which is contrary to the general perception of a single ventral branch. The initial dual innervation pattern later changes into an adult-like single branch pattern following the retraction of the superficial branch. The modified intercostal nerves consist of the canonical ventral branches and novel branches that run on the muscular surface of the thorax, which sprout from the lateral cutaneous branches. We formulated the embryonic branching pattern into the hypothetical ramification model of the human spinal nerve so that the branching pattern is compatible with the developmental context of the target muscles. In our model, every spinal nerve consists of three components: (1) segmental branches that innervate the primaxial muscles, including the dorsal rami, and short branches and long superficial anterior branches from the ventral rami; (2) plexus-forming intramural branches, the serial homolog of the canonical intercostal nerves, which innervate the abaxial portion of the body wall; and (3) plexus-forming extramural branches, the series of novel branches located outside of the body wall, which innervate the girdle and limb muscles. The selective elaboration or deletion of each component successfully explains the reasoning for the standard morphology and variability of the spinal nerve. Therefore, our model brings a novel understanding of spinal nerve development and valuable information for basic and clinical sciences regarding the diverse branching patterns of the spinal nerve.

Background Predicting time to renal replacement therapy (RRT) is important in patients at high risk for end-stage kidney disease. We developed and validated machine learning models for predicting the time to RRT and compared its accuracy with conventional prediction methods that uses the rate of estimated glomerular filtration rate (eGFR) decline. Methods Data of adult chronic kidney disease (CKD) patients who underwent hemodialysis at Oita University Hospital from April 2016 to March 2021 were extracted from electronic medical records ( N  = 135). A new machine learning predictor was compared with the established prediction method that uses the eGFR decline rate and the accuracy of the prediction models was determined using the coefficient of determination (R 2 ). The data were preprocessed and split into training and validation datasets. We created multiple machine learning models using the training data and evaluated their accuracy using validation data. Furthermore, we predicted the time to RRT using a conventional prediction method that uses the eGFR decline rate for patients who had measured eGFR three or more times in two years and evaluated its accuracy. Results The least absolute shrinkage and selection operator regression model exhibited moderate accuracy with an R 2 of 0.60. By contrast, the conventional prediction method was found to be extremely low with an R 2 of -17.1. Conclusions The significance of this study is that it shows that machine learning can predict time to RRT moderately well with continuous values from data at a single time point. This approach outperforms the conventional prediction method that uses eGFR time series data and presents new avenues for CKD treatment.

Embryonic stem (ES) cells self-renew as coherent colonies in which cells maintain tight cell-cell contact. Although intercellular communications are essential to establish the basis of cell-specific identity, molecular mechanisms underlying intrinsic cell-cell interactions in ES cells at the signaling level remain underexplored. Here we show that endogenous Rho signaling is required for the maintenance of cell-cell contacts in ES cells. siRNA-mediated loss of function experiments demonstrated that Rock, a major effector kinase downstream of Rho, played a key role in the formation of cell-cell junctional assemblies through regulation of myosin II by controlling a myosin light chain phosphatase. Chemical engineering of this signaling axis by a Rock-specific inhibitor revealed that cell-cell adhesion was reversibly controllable and dispensable for self-renewal of mouse ES cells as confirmed by chimera assay. Furthermore, a novel culture system combining a single synthetic matrix, defined medium, and the Rock inhibitor fully warranted human ES cell self-renewal independent of animal-derived matrices, tight cell contacts, or fibroblastic niche-forming cells as determined by teratoma formation assay. These findings demonstrate an essential role of the Rho-Rock-Myosin signaling axis for the regulation of basic cell-cell communications in both mouse and human ES cells, and would contribute to advance in medically compatible xeno-free environments for human pluripotent stem cells.