AptaTrans: a deep neural network for predicting aptamer-protein interaction using pretrained encoders.

BACKGROUND: Aptamers, which are biomaterials comprised of single-stranded DNA/RNA that form tertiary structures, have significant potential as next-generation materials, particularly for drug discovery. The systematic evolution of ligands by exponential enrichment (SELEX) method is a critical in vitro technique employed to identify aptamers that bind specifically to target proteins. While advanced SELEX-based methods such as Cell- and HT-SELEX are available, they often encounter issues such as extended time consumption and suboptimal accuracy. Several In silico aptamer discovery methods have been proposed to address these challenges. These methods are specifically designed to predict aptamer-protein interaction (API) using benchmark datasets. However, these methods often fail to consider the physicochemical interactions between aptamers and proteins within tertiary structures. RESULTS: In this study, we propose AptaTrans, a pipeline for predicting API using deep learning techniques. AptaTrans uses transformer-based encoders to handle aptamer and protein sequences at the monomer level. Furthermore, pretrained encoders are utilized for the structural representation. After validation with a benchmark dataset, AptaTrans has been integrated into a comprehensive toolset. This pipeline synergistically combines with Apta-MCTS, a generative algorithm for recommending aptamer candidates. CONCLUSION: The results show that AptaTrans outperforms existing models for predicting API, and the efficacy of the AptaTrans pipeline has been confirmed through various experimental tools. We expect AptaTrans will enhance the cost-effectiveness and efficiency of SELEX in drug discovery. The source code and benchmark dataset for AptaTrans are available at https://github.com/pnumlb/AptaTrans .

Automated algorithm development to assess survival of human neurons using longitudinal single-cell tracking: Application to synucleinopathy.

The development of phenotypic assays with appropriate analyses is an important step in the drug discovery process. Assays using induced pluripotent stem cell (iPSC)-derived human neurons are emerging as powerful tools for drug discovery in neurological disease. We have previously shown that longitudinal single cell tracking enabled the quantification of survival and death of neurons after overexpression of α-synuclein with a familial Parkinson's disease mutation (A53T). The reliance of this method on manual counting, however, rendered the process labor intensive, time consuming and error prone. To overcome these hurdles, we have developed automated detection algorithms for neurons using the BioStation CT live imaging system and CL-Quant software. In the current study, we use these algorithms to successfully measure the risk of neuronal death caused by overexpression of α-synuclein (A53T) with similar accuracy and improved consistency as compared to manual counting. This novel method also provides additional key readouts of neuronal fitness including total neurite length and the number of neurite nodes projecting from the cell body. Finally, the algorithm reveals the neuroprotective effects of brain-derived neurotrophic factor (BDNF) treatment in neurons overexpressing α-synuclein (A53T). These data show that an automated algorithm improves the consistency and considerably shortens the analysis time of assessing neuronal health, making this method advantageous for small molecule screening for inhibitors of synucleinopathy and other neurodegenerative diseases.

Human chemically-derived hepatic progenitors (hCdHs) as a source of liver organoid generation: Application in regenerative medicine, disease modeling, and toxicology testing.

BACKGROUND & AIMS: Several types of human stem cells from embryonic (ESCs) and induced pluripotent (iPSCs) to adult tissue-specific stem cells are commonly used to generate 3D liver organoids for modeling tissue physiology and disease. We have recently established a protocol for direct conversion of primary human hepatocytes (hPHs) from healthy donor livers into bipotent progenitor cells (hCdHs). Here we extended this culture system to generate hCdH-derived liver organoids for diverse biomedical applications. METHODS: To obtain hCdHs, hPHs were cultured in reprogramming medium containing A83-01 and CHIR99021 for 7 days. Liver organoids were established from hCdHs (hCdHOs) and human liver cells (hLOs) using the same donor livers for direct comparison, as well as from hiPSCs. Organoid properties were analyzed by standard in vitro assays. Molecular changes were determined by RT-qPCR and RNA-seq. Clinical relevance was evaluated by transplantation into FRG mice, modeling of alcohol-related liver disease (ARLD), and in vitro drug-toxicity tests. RESULTS: hCdHs were clonally expanded as organoid cultures with low variability between starting hCdH lines. Similar to the hLOs, hCdHOs stably maintained stem cell phenotype based on accepted criteria. However, hCdHOs had an advantage over hLOs in terms of EpCAM expression, efficiency of organoid generation and capacity for directed hepatic differentiation as judged by molecular profiling, albumin secretion, glycogen accumulation, and CYP450 activities. Accordingly, FRG mice transplanted with hCdHOs survived longer than mice injected with hLOs. When exposed to ethanol, hCdHOs developed stronger ARLD phenotype than hLOs as evidenced by transcriptional profiling, lipid accumulation and mitochondrial dysfunction. In drug-induced injury assays in vitro, hCdHOs showed a similar or higher sensitivity response than hPHs. CONCLUSION: hCdHOs provide a novel patient-specific stem cell-based platform for regenerative medicine, toxicology testing and modeling liver diseases.

A Brain-Penetrant Stearoyl-CoA Desaturase Inhibitor Reverses α-Synuclein Toxicity.

Increasing evidence has shown that Parkinson's disease (PD) impairs midbrain dopaminergic, cortical and other neuronal subtypes in large part due to the build-up of lipid- and vesicle-rich α-synuclein (αSyn) cytotoxic inclusions. We previously identified stearoyl-CoA desaturase (SCD) as a potential therapeutic target for synucleinopathies. A brain-penetrant SCD inhibitor, YTX-7739, was developed and has entered Phase 1 clinical trials. Here, we report the efficacy of YTX-7739 in reversing pathological αSyn phenotypes in various in vitro and in vivo PD models. In cell-based assays, YTX-7739 decreased αSyn-mediated neuronal death, reversed the abnormal membrane interaction of amplified E46K ("3K") αSyn, and prevented pathological phenotypes in A53T and αSyn triplication patient-derived neurospheres, including dysregulated fatty acid profiles and pS129 αSyn accumulation. In 3K PD-like mice, YTX-7739 crossed the blood-brain barrier, decreased unsaturated fatty acids, and prevented progressive motor deficits. Both YTX-7739 treatment and decreasing SCD activity through deletion of one copy of the SCD1 gene (SKO) restored the physiological αSyn tetramer-to-monomer ratio, dopaminergic integrity, and neuronal survival in 3K αSyn mice. YTX-7739 efficiently reduced pS129 + and PK-resistant αSyn in both human wild-type αSyn and 3K mutant mice similar to the level of 3K-SKO. Together, these data provide further validation of SCD as a PD therapeutic target and YTX-7739 as a clinical candidate for treating human α-synucleinopathies.

Pore-scale observations of natural hydrate-bearing sediments via pressure core sub-coring and micro-CT scanning.

Both intra-pore hydrate morphology and inter-pore hydrate distribution influence the physical properties of hydrate-bearing sediments, yet there has been no pore-scale observations of hydrate habit under pressure in preserved pressure core samples so far. We present for the first time a pore-scale micro-CT study of natural hydrate-bearing cores that were acquired from Green Canyon Block 955 in UT-GOM2-1 Expedition and preserved within hydrate pressure-temperature stability conditions throughout sub-sampling and imaging processes. Measured hydrate saturation in the sub-samples, taken from units expected to have in-situ saturation of 80% or more, ranges from 3 ± 1% to 56 ± 11% as interpreted from micro-CT images. Pore-scale observations of gas hydrate in the sub-samples suggest that hydrate in silty sediments at the Gulf of Mexico is pore-invasive rather than particle displacive, and hydrate particles in these natural water-saturated samples are pore-filling with no evidence of grain-coating. Hydrate can form a connected 3D network and provide mechanical support for the sediments even without cementation. The technical breakthrough to directly visualize particle-level hydrate pore habits in natural sediments reported here sheds light on future investigations of pressure- and temperature-sensitive processes including hydrate-bearing sediments, dissolved gases, and other biochemical processes in the deep-sea environment.

The histone H3-lysine 4-methyltransferase Mll4 regulates the development of growth hormone-releasing hormone-producing neurons in the mouse hypothalamus.

In humans, inactivating mutations in MLL4, which encodes a histone H3-lysine 4-methyltransferase, lead to Kabuki syndrome (KS). While dwarfism is a cardinal feature of KS, the underlying etiology remains unclear. Here we report that Mll4 regulates the development of growth hormone-releasing hormone (GHRH)-producing neurons in the mouse hypothalamus. Our two Mll4 mutant mouse models exhibit dwarfism phenotype and impairment of the developmental programs for GHRH-neurons. Our ChIP-seq analysis reveals that, in the developing mouse hypothalamus, Mll4 interacts with the transcription factor Nrf1 to trigger the expression of GHRH-neuronal genes. Interestingly, the deficiency of Mll4 results in a marked reduction of histone marks of active transcription, while treatment with the histone deacetylase inhibitor AR-42 rescues the histone mark signature and restores GHRH-neuronal production in Mll4 mutant mice. Our results suggest that the developmental dysregulation of Mll4-directed epigenetic control of transcription plays a role in the development of GHRH-neurons and dwarfism phenotype in mice.

Rod Fracture Causing Relief of Back Pain That Developed After Adult Lumbar Degenerative Flat-Back Correction Surgery: A Case Report.

A 73-year-old woman underwent deformity correction surgery (anterior lumbar interbody fusion of L2-L3-L4-L5-S1, pedicle subtraction osteotomy at L4, and posterior screw fixation from T10 to the pelvis) due to lumbar degenerative flat-back. Following the operation, the patient experienced pain in her back and buttocks, for which she regularly took medications. She reported frequently feeling a heavy and stretched sensation of pain after the operation in those areas, which made her regret undergoing the operation. However, at 33 months postoperatively, she reported that one day, while getting up from a chair, she felt a crack in her back, which was followed by an improvement in her back and buttock pain; thereafter, she stopped taking pain medications. Follow-up radiography revealed a bilateral rod fracture at the L4-5 level on the right side and at the L3-4 level on the left side. The overall pelvic parameters, except pelvic incidence, slightly changed after the rod fracture. Therefore, the broken rod was replaced and another rod was added to the broken rod area; however, the changed pelvic parameters were not corrected further during the reoperation. Following the reoperation, the patient showed improvements and she no longer required pain medication.

Integration of triaxial testing and pore-scale visualization of methane hydrate bearing sediments.

Understanding mechanical interactions between hydrate and hosting sediments is critical for evaluating formation stability and associated environmental impacts of hydrate-bearing sediments during gas production. While core-scale studies of hydrate-bearing sediments are readily available and some explanations of observed results rely on pore-scale behavior of hydrate, actual pore-scale observations supporting the larger-scale phenomena are rarely available for hydrate-bearing sediments, especially with methane as guest molecules. The primary reasons for the scarcity include the challenge of developing tools for small-scale testing apparatus and pore-scale visualization capability. We present a testing assembly that combines pore-scale visualization and triaxial test capability of methane hydrate-bearing sediments. This testing assembly allows temperature regulation and independent control of four pressures: influent and effluent pore pressure, confining pressure, and axial pressure. Axial and lateral effective stresses can be applied independently to a 9.5 mm diameter and 19 mm long specimen while the pore pressure and temperature are controlled to maintain the stability of methane hydrate. The testing assembly also includes an X-ray transparent beryllium core holder so that 3D computed tomography scanning can be conducted during the triaxial loading. This testing assembly permits pore-scale exploration of hydrate-sediment interaction in addition to the traditional stress-strain relationship. Exemplary outcomes are presented to demonstrate applications of the testing assembly on geomechanical property estimations of methane-hydrate bearing sediments.

Transforaminal Epiduroscopic Basivertebral Nerve Laser Ablation for Chronic Low Back Pain Associated with Modic Changes: A Preliminary Open-Label Study.

Background: Chronic low back pain (CLBP) arising from degenerative disc disease continues to be a challenging clinical and diagnostic problem whether treated with nonsurgical, pain intervention, or motion-preserving stabilization and arthrodesis. Methods: Fourteen patients with CLBP, greater than 6 months, unresponsive to at least 4 months of conservative care were enrolled. All patients were treated successfully following screening using MRI findings of Modic type I or II changes and positive confirmatory provocative discography to determine the affected levels. All patients underwent ablation of the basivertebral nerve (BVN) using 1414 nm Nd:YAG laser-assisted energy guided in a transforaminal epiduroscopic approach. Macnab's criteria and visual analog scale (VAS) score were collected retrospectively at each follow-up interval. Results: The mean age was 46 ± 9.95 years. The mean symptoms duration was 21.21 ± 21.87 months. The mean follow-up was 15.3 ± 2.67 months. The preoperative VAS score of 7.79 ± 0.97 changed to 1.92 ± 1.38, postoperatively (P < 0.01). As per Macnab's criteria, seven patients (50%) had excellent, six patients (42.85%) had good, and one patient (7.14%) had fair outcomes. Conclusion: The transforaminal epiduroscopic basivertebral nerve laser ablation (TEBLA) appears to be a promising option in carefully selected patients with CLBP associated with the Modic changes.

Full Endoscopic Lumbar Discectomy using the Calcification Floating Technique for Symptomatic Partially Calcified Lumbar Herniated Nucleus Pulposus.

BACKGROUND: Partially calcified lumbar herniated nucleus pulposus (HNP) can cause severe radiating pain and neurologic symptoms requiring surgical treatment. As it is not safe to enforce conventional endoscopic lumbar discectomy using trephine or burr to remove the partially calcified disc, we report a calcification floating technique using a working channel for the treatment of these cases. METHODS: We retrospectively analyzed 31 patients who underwent full endoscopic discectomy using this technique for partially calcified lumbar HNP between April 2009 and June 2013. Calcification floating technique was performed by inserting the working channel around the partially calcified HNP and then rotating the working channel around it to remove the lesion. We analyzed the outcomes with a Visual Analogue Scale (VAS), Oswestry Disability Index (ODI), and complication rate. RESULTS: The mean follow-up period was 26.58 ± 11.2 months. The interlaminar approach was used in 15 cases, and the transforaminal approach was used in 16 cases. The mean VAS of 8.19 ± 0.65 before surgery was decreased to 1.29 ± 0.69 at the last follow-up. The mean ODI score before surgery was decreased at the last follow-up, from 41.32 ± 2.87 to 9.87 ± 3.47. Mean operative duration was 45 ± 12 minutes per level. None of the patients required revision surgery or developed any major complication. CONCLUSIONS: Calcification floating technique is a safe and effective method for the treatment of partially calcified lumbar HNP.

Suprapedicular Circumferential Opening Technique of Percutaneous Endoscopic Transforaminal Lumbar Discectomy for High Grade Inferiorly Migrated Lumbar Disc Herniation.

PURPOSE: To evaluate the efficacy of suprapedicular circumferential opening technique (SCOT) of percutaneous endoscopic transforaminal lumbar discectomy (PETLD) for high grade inferiorly migrated lumbar disc herniation. MATERIAL AND METHODS: Eighteen consecutive patients who presented with back and leg pain with a single-level high grade inferiorly migrated lumbar disc herniation were included. High grade inferiorly migrated disc was removed by the SCOT through PETLD approach. Outcome evaluation was done with visual analog scale (VAS) and Mac Nab's criteria. RESULT: There were 14 males and 4 females. The mean age of patients was 53.3 ± 14.12 years. One, 4, and 13 patients had disc herniation at L1-2, L3-4, and L4-5 levels, respectively, on MRI, which correlated with clinical findings. The mean follow-up duration was 8.4 ± 4.31 months. According to Mac Nab's criteria, 9 patients (50%) reported excellent and the remaining 9 patients (50%) reported good outcomes. The mean preoperative and postoperative VAS for leg pain were 7.36 ± 0.73 and 1.45 ± 0.60, respectively (p < 0.001). Improvement in outcomes was maintained even at final follow-up. There was no complication. CONCLUSION: In this preliminary study we achieved good to excellent clinical results using the SCOT of PETLD for high grade inferiorly migrated lumbar disc herniation.

Functional Limitations Due to Stiffness After Long-Level Spinal Instrumented Fusion Surgery to Correct Lumbar Degenerative Flat Back.

STUDY DESIGN: A retrospective analysis of functional limitations due to stiffness after long-level spinal instrumented fusion surgery to correct lumbar degenerative flat back was performed. OBJECTIVE: To analysis the functional limitations in patients treated surgically for adult lumbar degenerative flat back (ALDFB) with long-level instrumented fusion to the sacrum or pelvis. SUMMARY OF BACKGROUND DATA: Long-level instrumented fusion for ALDFB decreases back pain and spinal deformity. On the contrary, this surgery considerably eliminates spinal range of motion. This may have the potential to impair function and ability to perform activities of daily living (ADLs). METHODS: Consecutive 44 patients who underwent long-level instrumented fusion to the sacrum or pelvis for ALDFB were retrospectively included in this study. All patients were followed up for a minimum of 13 months. The Lumbar Stiffness Disability Index for Korean Lifestyle and Oswestry Disability Index were administered and analyzed to assess the impact of spinal stiffness on daily living. Cohorts were defined based on the upper instrumented vertebrae (above T10 [group 1] or below L1 [group 2]) and lower instrumented vertebrae (S1 pedicle screw [group S] or iliac bolt screw [group I]). RESULTS: All patients showed deteriorated postoperative ADLs compared to preoperative values. Group 1 showed deterioration postoperatively compared to group 2. Group 1 showed deteriorated postoperative ADLs compared to preoperative values. In group 2, question 5 and 7 showed deterioration postoperatively compared to preoperative values, and question 2 and 10 showed improvement postoperatively compared to preoperative values. Group I showed deterioration postoperatively compared to group S. CONCLUSION: This study will hopefully allow surgeons to provide patients with ALDFB with a more informed explanation of expected surgery effects on specific ADLs. LEVEL OF EVIDENCE: 3.

Lumbar chronic subdural hematoma mimicking an intradural extramedullary tumor: A case report.

BACKGROUND: Chronic spinal subdural hematomas are extremely rare with only 28 cases reported in the literature. Nevertheless, they should be considered among the differential diagnoses for spinal intradural/extramedullary lesions. CASE REPORT: A 65-year-old male presented with progressive back pain and right S1 radiculopathy. Magnetic resonance imaging scan revealed a right-sided posterolateral intradural/extramedullary lesion at the L5-S1 level. It was hyperintense on T1 and hypointense on T2-weighted images; on the short TI inversion recovery sequence it was hyperintense. The lesion was excised through a right L5 hemilaminectomy, and the patient was neurologically intact postoperatively. Histopathology revealed a chronic subdural hematoma. CONCLUSION: Chronic spinal subdural hematoma can mimic intradural extramedullary spinal tumors even in the absence of trauma and/or coagulopathies.

Abdominal Flank Bulging after Lateral Retroperitoneal Approach: A Case Report.

The lateral transpsoas approach to access the vertebrae obviates the need for an approach surgeon and minimizes muscular disruption, thus allowing for quicker recovery. Several reports on the lateral transpsoas procedure have described few complications. However, the development of an unsightly and painful abdominal flank bulge is a largely under-recognized and very rare complication of the lateral transpsoas approach. A 59-year-old man suffered from back pain and bilateral posterior leg pain. Computed tomography (CT) scan and MRI showed retrolisthesis at L3-4, L2 wedge vertebrae with kyphosis, left L4 screw loosening, and L3-4 disc herniation with central canal stenosis. L2 corpectomy and L3-4 DLIF and posterior fusion to T12 for kyphosis correction were performed. For the lateral approach, resection of the T11 rib was performed. One month later, he developed left abdominal flank bulging below the lateral approach site, which was aggravated by walking, coughing, defecating, constipation, and eating. CT scan showed left abdominal flank bulging accompanied by abdominal muscle thinning. We believe that this complication is caused by denervation of the abdominal musculature after injury to the T11 intercostal nerves.

What Is the More Appropriate Proximal Fusion Level for Adult Lumbar Degenerative Flat Back?

OBJECTIVE: To determine the optimal proximal fusion level after long instrumented fusion to the sacrum for lumbar degenerative flat back. METHODS: Data from 70 patients with lumbar degenerative flat back were reviewed retrospectively. Three groups were designated according to the upper instrumented vertebrae (UIV): group 1 (UIV = T10 or above), group 2 (UIV = T11-12), and group 3 (UIV = L1 or below). Pre- and postoperative pelvic parameters, degree of correction, and prevalence of proximal junctional kyphosis (PJK) and its risk factors were evaluated. RESULTS: The prevalence of PJK was 27.1% (average 35.5 months of follow-up). Preoperative pelvic incidence (PI) and sacral slope (SS) in group 1 were higher in the PJK group than in the non-PJK group (P = 0.03 and P = 0.001, respectively). Preoperative thoracolumbar (TL) in group 3 was higher in the PJK group than in the non-PJK group (P = 0.01). Postoperative pelvic tilt (PT) was lower (<20°) in the non-PJK group than in the PJK group (P = 0.025 in group 3). Postoperative TL in group 3 was lower than in the non-PJK group (P = 0.024). CONCLUSIONS: If the PI is ≥50°, TL kyphosis is ≥5°, and SS is ≥20°, the UIV should be raised above T10 up to the midthoracic level. If the PI is ≥50°, SS is ≤20°, and thoracic kyphosis (TK) is normal despite TL kyphosis, the UIV should be at T10. Even if the PI is ≥50°, TK is normal, and there is no TL kyphosis, the UIV should be set at L1 or below. Regardless of the UIV, the postoperative PT should be ≤20°.

Social deficits in IRSp53 mutant mice improved by NMDAR and mGluR5 suppression.

Social deficits are observed in diverse psychiatric disorders, including autism spectrum disorders and schizophrenia. We found that mice lacking the excitatory synaptic signaling scaffold IRSp53 (also known as BAIAP2) showed impaired social interaction and communication. Treatment of IRSp53(-/-) mice, which display enhanced NMDA receptor (NMDAR) function in the hippocampus, with memantine, an NMDAR antagonist, or MPEP, a metabotropic glutamate receptor 5 antagonist that indirectly inhibits NMDAR function, normalized social interaction. This social rescue was accompanied by normalization of NMDAR function and plasticity in the hippocampus and neuronal firing in the medial prefrontal cortex. These results, together with the reduced NMDAR function implicated in social impairments, suggest that deviation of NMDAR function in either direction leads to social deficits and that correcting the deviation has beneficial effects.

Multi-property characterization chamber for geophysical-hydrological investigations of hydrate bearing sediments.

With the increase in the interest of producing natural gas from methane hydrates as well as potential risks of massive hydrate dissociation in the context of global warming, studies have recently shifted from pure hydrate crystals to hydrates in sediments. Such a research focus shift requires a series of innovative laboratory devices that are capable of investigating various properties of hydrate-bearing sediments (HBS). This study introduces a newly developed high pressure testing chamber, i.e., multi-property characterization chamber (MPCC), that allows simultaneous investigation of a series of fundamental properties of HBS, including small-strain stiffness (i.e., P- and S-waves), shear strength, large-strain deformation, stress-volume responses, and permeability. The peripheral coolant circulation system of the MPCC permits stable and accurate temperature control, while the core holder body, made of aluminum, enables X-ray computer tomography scanning to be easily employed for structural and morphological characterization of specimens. Samples of hydrate-bearing sediments are held within a rubber sleeve inside the chamber. The thick sleeve is more durable and versatile than thin membranes while also being much softer than oedometer-type chambers that are incapable of enabling flow tests. Bias introduced by the rubber sleeve during large deformation tests are also calibrated both theoretically and experimentally. This system provides insight into full characterization of hydrate-bearing sediments in the laboratory, as well as pressure core technology in the field.

Activated retinoid receptors are required for the migration and fate maintenance of subsets of cortical neurons.

Layer-specific cortical neurons are essential components of local, intracortical and subcortical circuits and are specified by complex signaling pathways acting on cortical progenitors. However, whether extrinsic signals contribute to postmitotic cortical neuronal development is unclear. Here we show in mice that retinoic acid (RA) receptors are activated in newly born migrating cortical neurons indicative of endogenous RA in the cortex. Disruption of RA signaling in postmitotic neurons by dominant-negative retinoid receptor RAR403 expression specifically delays late-born cortical neuron migration in vivo. Moreover, prospective layer V-III neurons that express RAR403 fail to maintain their fates and instead acquire characteristics of layer II neurons. This latter phenotype is rescued by active forms of ß-catenin at central and caudal but not rostral cortical regions. Taken together, these observations suggest that RA signaling pathways operate postmitotically to regulate the onset of radial migration and to consolidate regional differences in cortical neuronal identity.

Gde2 regulates cortical neuronal identity by controlling the timing of cortical progenitor differentiation.

The mammalian cortex is a multilaminar structure consisting of specialized layer-specific neurons that form complex circuits throughout the brain and spinal cord. These neurons are generated in a defined sequence dictated by their birthdate such that early-born neurons settle in deep cortical layers whereas late-born neurons populate more superficial layers. Cortical neuronal birthdate is partly controlled by an intrinsic clock-type mechanism; however, the role of extrinsic factors in the temporal control of cell-cycle exit is less clear. Here, we show that Gde2, a six-transmembrane protein that induces spinal neuronal differentiation, is expressed in the developing cortex throughout cortical neurogenesis. In the absence of Gde2, cortical progenitors fail to exit the cell cycle on time, remain cycling, accumulate and exit the cell cycle en masse towards the end of the neurogenic period. These dynamic changes in cell-cycle progression cause deficits and delays in deep-layer neuronal differentiation and robust increases in superficial neuronal numbers. Gde2(-/-) cortices show elevated levels of Notch signaling coincident with when progenitors fail to differentiate, suggesting that abnormal Notch activation retains cells in a proliferative phase that biases them to superficial fates. However, no change in Notch signaling is observed at the time of increased cell-cycle exit. These observations define a key role for Gde2 in controlling cortical neuronal fates by regulating the timing of neurogenesis, and show that loss of Gde2 uncovers additional mechanisms that trigger remaining neuronal progenitors to differentiate at the end of the neurogenic period.