Developmental Timeline Research Articles

Advances in the Differentiation of hiPSCs into Cerebellar Neuronal Cells.

The cerebellum has historically been primarily associated with the regulation of precise motor functions. However, recent findings suggest that it also plays a pivotal role in the development of advanced cognitive functions, including learning, memory, and emotion regulation. Pathological changes in the cerebellum, whether congenital hereditary or acquired degenerative, can result in a diverse spectrum of disorders, ranging from genetic spinocerebellar ataxias to psychiatric conditions such as autism, and schizophrenia. While studies in animal models have significantly contributed to our understanding of the genetic networks governing cerebellar development, it is important to note that the human cerebellum follows a protracted developmental timeline compared to the neocortex. Consequently, employing animal models to uncover human-specific molecular events in cerebellar development presents significant challenges. The emergence of human induced pluripotent stem cells (hiPSCs) has provided an invaluable tool for creating human-based culture systems, enabling the modeling and analysis of cerebellar physiology and pathology. hiPSCs and their differentiated progenies can be derived from patients with specific disorders or carrying distinct genetic variants. Importantly, they preserve the unique genetic signatures of the individuals from whom they originate, allowing for the elucidation of human-specific molecular and cellular processes involved in cerebellar development and related disorders. This review focuses on the technical advancements in the utilization of hiPSCs for the generation of both 2D cerebellar neuronal cells and 3D cerebellar organoids.

Anatomical and molecular development of the human primary visual cortex.

The human primary visual cortex (V1) development is pivotal to understanding cortical maturation and neuroplasticity. Theories on V1 development range from early maturation models, which emphasize the early peak of synapses in infancy, to those suggesting an extended developmental timeline where key plasticity mechanisms continue to mature well into adulthood. Classic histological approaches have supported early development, while recent molecular studies highlight prolonged or multiple windows of plasticity, indicating that V1 remains susceptible to experience-dependent modifications beyond childhood. This review consolidates findings from both anatomical and molecular studies, tracing the development of V1 from prenatal stages through aging. The evidence reveals that human V1 develops across multiple timescales, with some aspects maturing early and others gradually changing across the lifespan. Reflecting on Cajal's early work, this review underscores the importance of methodological advancements in revealing the intricate details of V1's development.

Retinal Input Is Required for the Maintenance of Neuronal Laminae in the Ventrolateral Geniculate Nucleus.

Retinal ganglion cell (RGC) axons provide direct input into several brain regions, including the dorsal lateral geniculate nucleus (dLGN), which is important for image-forming vision, and the ventrolateral geniculate nucleus (vLGN), which is associated with nonimage-forming vision. Through both activity- and morphogen-dependent mechanisms, retinal inputs play important roles in the development of dLGN, including the refinement of retinal projections, morphological development of thalamocortical relay cells (TRCs), timing of corticogeniculate innervation, and recruitment and distribution of inhibitory interneurons. In contrast, little is known about the role of retinal inputs in the development of vLGN. Grossly, vLGN is divided into two domains, the retinorecipient external vLGN (vLGNe) and nonretinorecipient internal vLGN (vLGNi). Studies previously found that vLGNe consists of transcriptionally distinct GABAergic subtypes distributed into at least four adjacent laminae. At present, it remains unclear whether retinal inputs influence the development of these cell-type-specific neuronal laminae in vLGNe. Here, we elucidated the developmental timeline for these laminae in the mouse vLGNe, and results indicate that these laminae are specified at or before birth. We observed that mutant mice without retinal inputs have a normal laminar distribution of GABAergic cells at birth; however, after the first week of postnatal development, these mutants exhibited a dramatic disruption in the laminar organization of inhibitory neurons and clear boundaries between vLGNe and vLGNi. Overall, our results show that while the formation of cell-type-specific layers in mouse vLGNe does not depend on RGC inputs, retinal signals are critical for their maintenance.

A Five-Year Review of Newborn Screening for Spinal Muscular Atrophy in the State of Utah: Lessons Learned.

Spinal muscular atrophy (SMA) is an autosomal recessive condition characterized by alpha motor neuron degeneration in the spinal cord anterior horn. Clinical symptoms manifest in the first weeks to months of life in the most severe cases, resulting in progressive symmetrical weakness and atrophy of the proximal voluntary muscles. Approximately 95% of SMA patients present with homozygous deletion of the SMN1 gene. With multiple available therapies preventing symptom development and slowing disease progression, newborn screening for SMA is essential to identify at-risk individuals. From 2018 to 2023, a total of 239,844 infants were screened. 13 positive screens were confirmed to have SMA. An additional case was determined to be a false positive. We are not aware of any false-negative cases. All patients were seen promptly, with diagnosis confirmed within 1 week of the initial clinical visit. Patients were treated with nusinersen or onasemnogene abeparvovec. Treated patients with two copies of SMN2 are meeting important developmental milestones inconsistent with the natural history of type 1 SMA. Patients with 3-4 copies of SMN2 follow normal developmental timelines. Newborn screening is an effective tool for the early identification and treatment of patients with SMA. Presymptomatic treatment dramatically shifts the natural history of SMA, with most patients meeting appropriate developmental milestones. Patients with two copies of SMN2 identified through newborn screening constitute a neurogenetic emergency. Due to the complexities of follow-up, a multidisciplinary team, including close communication with the newborn screening program, is required to facilitate timely diagnosis and treatment.

Development of neuronal timescales in human cortical organoids and rat hippocampus dissociated cultures.

To support complex cognition, neuronal circuits must integrate information across multiple temporal scales, ranging from milliseconds to decades. Neuronal timescales describe the duration over which activity within a network persists, posing a putative explanatory mechanism for how information might be integrated over multiple temporal scales. Little is known about how timescales develop in human neural circuits or other model systems, limiting insight into how the functional dynamics necessary for cognition emerge. In our work, we show that neuronal timescales develop in a nonlinear fashion in human cortical organoids, which is partially replicated in dissociated rat hippocampus cultures. We use spectral parameterization of spiking activity to extract an estimate of neuronal timescale that is unbiased by coevolving oscillations. Cortical organoid timescales begin to increase around month 6 postdifferentiation. In rodent hippocampal dissociated cultures, we see that timescales decrease from in vitro days 13-23 before stabilizing. We speculate that cortical organoid development over the duration studied here reflects an earlier stage of a generalized developmental timeline in contrast to the rodent hippocampal cultures, potentially accounting for differences in timescale developmental trajectories. The fluctuation of timescales might be an important developmental feature that reflects the changing complexity and information capacity in developing neuronal circuits.NEW & NOTEWORTHY Neuronal timescales describe the persistence of activity within a network of neurons. Timescales were found to fluctuate with development in two model systems. In cortical organoids timescales increased, peaked, and then decreased throughout development; in rat hippocampal dissociated cultures timescales decreased over development. These distinct developmental models overlap to highlight a critical window in which timescales lengthen and contract, potentially indexing changes in the information capacity of neuronal systems.

Cancer-specific epigenome identifies oncogenic hijacking by nuclear factor I family proteins for medulloblastoma progression

Normal cells coordinate proliferation and differentiation by precise tuning of gene expression based on the dynamic shifts of the epigenome throughout the developmental timeline. Although non-mutational epigenetic reprogramming is an emerging hallmark of cancer, the epigenomic shifts that occur during the transition from normal to malignant cells remain elusive. Here, we capture the epigenomic changes that occur during tumorigenesis in a prototypic embryonal brain tumor, medulloblastoma. By comparing the epigenomes of the different stages of transforming cells in mice, we identify nuclear factor I family of transcription factors, known to be cell fate determinants in development, as oncogenic regulators in the epigenomes of precancerous and cancerous cells. Furthermore, genetic and pharmacological inhibition of NFIB validated a crucial role of this transcription factor by disrupting the cancer epigenome in medulloblastoma. Thus, this study exemplifies how epigenomic changes contribute to tumorigenesis via non-mutational mechanisms involving developmental transcription factors.

MAPPING ALZHEIMER'S DISEASE PSEUDO-PROGRESSION WITH MULTIMODAL BIOMARKER TRAJECTORY EMBEDDINGS.

Alzheimer's Disease (AD) is a neurodegenerative disorder characterized by progressive cognitive degeneration and motor impairment, affecting millions worldwide. Mapping the progression of AD is crucial for early detection of loss of brain function, timely intervention, and development of effective treatments. However, accurate measurements of disease progression are still challenging at present. This study presents a novel approach to understanding the heterogeneous pathways of AD through longitudinal biomarker data from medical imaging and other modalities. We propose an analytical pipeline adopting two popular machine learning methods from the single-cell transcriptomics domain, PHATE and Slingshot, to project multimodal biomarker trajectories to a low-dimensional space. These embeddings serve as our pseudotime estimates. We applied this pipeline to the Alzheimer's Disease Neuroimaging Initiative (ADNI) dataset to align longitudinal data across individuals at various disease stages. Our approach mirrors the technique used to cluster single-cell data into cell types based on developmental timelines. Our pseudotime estimates revealed distinct patterns of disease evolution and biomarker changes over time, providing a deeper understanding of the temporal dynamics of AD. The results show the potential of the approach in the clinical domain of neurodegenerative diseases, enabling more precise disease modeling and early diagnosis.

Positioning adolescence in the developmental timeline.

Adolescence, the second decade of life, bridges childhood and adulthood, but also represents a host of unique experiences that impact health and well-being. Lifespan theories often emphasize the continuity of individual characteristics and their contexts from childhood to adolescence, underscoring the distal influence of childhood experiences. Yet, adolescence is marked by transitions that may provoke discontinuities, particularly within individuals, their contexts, and their interactions within those contexts. These discontinuities occur at varied times, orders, and intensities for individualyouth, suggesting that adolescence may be a developmental turning point where earlier life experiences may be mediated, reversed, or transformed by proximal events. This perspective piece emphasizes the importance of considering transitions, discontinuities, and developmental turning points in adolescence as well as their potential to explain heterogeneity in adolescent and adult outcomes. We explore one biological and one contextual transition in adolescence and highlight innovative theories and methods for investigating continuity and discontinuity dynamics across development, which could lead to new insights related to the adolescent period and its importance in shaping future life trajectories.

Hydrogels in Gene Delivery Techniques for Regenerative Medicine and Tissue Engineering.

Hydrogels are 3D networks swollen with water. They are biocompatible, strong, and moldable and are emerging as a promising biomedical material for regenerative medicine and tissue engineering to deliver therapeutic genes. The excellent natural extracellular matrix simulation properties of hydrogels enable them to be co-cultured with cells or enhance the expression of viral or non-viral vectors. Its biocompatibility, high strength, and degradation performance also make the action process of carriers in tissues more ideal, making it an ideal biomedical material. It has been shown that hydrogel-based gene delivery technologies have the potential to play therapy-relevant roles in organs such as bone, cartilage, nerve, skin, reproductive organs, and liver in animal experiments and preclinical trials. This paper reviews recent articles on hydrogels in gene delivery and explains the manufacture, applications, developmental timeline, limitations, and future directions of hydrogel-based gene delivery techniques.

Dentate gyrus developmental timeline in CLN3del78/del78(Batten disease) mice

Dentate gyrus developmental timeline in CLN3del78/del78(Batten disease) mice

From vision to memory: How scene-sensitive regions support episodic memory formation during child development

Previous brain imaging studies have identified three brain regions that selectively respond to visual scenes, the parahippocampal place area (PPA), the occipital place area (OPA), and the retrosplenial cortex (RSC). There is growing evidence that these visual scene-sensitive regions process different types of scene information and may have different developmental timelines in supporting scene perception. How these scene-sensitive regions support memory functions during child development is largely unknown. We investigated PPA, OPA and RSC activations associated with episodic memory formation in childhood (5–7 years of age) and young adulthood, using a subsequent scene memory paradigm and a functional localizer for scenes. PPA, OPA, and RSC subsequent memory activation and functional connectivity differed between children and adults. Subsequent memory effects were found in activations of all three scene regions in adults. In children, however, robust subsequent memory effects were only found in the PPA. Functional connectivity during successful encoding was significant among the three regions in adults, but not in children. PPA subsequently memory activations and PPA-RSC subsequent memory functional connectivity correlated with accuracy in adults, but not children. These age-related differences add new evidence linking protracted development of the scene-sensitive regions to the protracted development of episodic memory.

Metabolic Determinants of Cerebellar Circuit Formation and Maintenance.

Cells configure their metabolism in a synchronized and timely manner to meet their energy demands throughout development and adulthood. Transitions of developmental stages are coupled to metabolic shifts, such that glycolysis is highly active during cell proliferation, whereas oxidative phosphorylation prevails in postmitotic states. In the cerebellum, metabolic transitions are remarkable given its protracted developmental timelines. Such distinctive feature, along with its high neuronal density and metabolic demands, make the cerebellum highly vulnerable to metabolic insults. Despite the expansion of metabolomic approaches to uncover biological mechanisms, little is known about the role of metabolism on cerebellar development and maintenance. To illuminate the intricate connections between metabolism, physiology, and cerebellar disorders, we examined here the impact of metabolism on cerebellar growth, maturation, and adulthood through the lens of inborn errors of metabolism.

The Impact of Maternal Obesity on Adipose Progenitor Cells.

The concept of Developmental Origin of Health and Disease (DOHaD) postulates that adult-onset metabolic disorders may originate from suboptimal conditions during critical embryonic and fetal programming windows. In particular, nutritional disturbance during key developmental stages may program the set point of adiposity and its associated metabolic diseases later in life. Numerous studies in mammals have reported that maternal obesity and the resulting accelerated growth in neonates may affect adipocyte development, resulting in persistent alterations in adipose tissue plasticity (i.e., adipocyte proliferation and storage) and adipocyte function (i.e., insulin resistance, impaired adipokine secretion, reduced thermogenesis, and higher inflammation) in a sex- and depot-specific manner. Over recent years, adipose progenitor cells (APCs) have been shown to play a crucial role in adipose tissue plasticity, essential for its development, maintenance, and expansion. In this review, we aim to provide insights into the developmental timeline of lineage commitment and differentiation of APCs and their role in predisposing individuals to obesity and metabolic diseases. We present data supporting the possible implication of dysregulated APCs and aberrant perinatal adipogenesis through epigenetic mechanisms as a primary mechanism responsible for long-lasting adipose tissue dysfunction in offspring born to obese mothers.

Electron Spin Resonance Probe Incorporation into Bioinks Permits Longitudinal Oxygen Imaging of Bioprinted Constructs

PurposeBioprinting is an additive manufacturing technology analogous to 3D printing. Instead of plastic or resin, cell-laden hydrogels are used to produce a construct of the intended biological structure. Over time, cells transform this construct into a functioning tissue or organ. The process of printing followed by tissue maturation is referred to as 4D bioprinting. The fourth dimension is temporal. Failure to provide living cells with sufficient amounts of oxygen at any point along the developmental timeline may jeopardize the bioprinting goals. Even transient hypoxia may alter cells' differentiation and proliferation or trigger apoptosis. Electron paramagnetic resonance (EPR) imaging modality is proposed to permit 4D monitoring of oxygen within bioprinted structures.ProceduresLithium octa-n-butoxy-phthalocyanine (LiNc-BuO) probes have been introduced into gelatin methacrylate (GelMA) bioink. GelMA is a cross-linkable hydrogel, and LiNc-BuO is an oxygen-sensitive compound that permits longitudinal oximetric measurements. The effects of the oxygen probe on printability have been evaluated. A digital light processing (DLP) bioprinter was built in the laboratory. Bioprinting protocols have been developed that consider the optical properties of the GelMA/LiNc-BuO composites. Acellular and cell-laden constructs have been printed and imaged. The post-printing effect of residual photoinitiator on oxygen depletion has been investigated.ResultsModels have been successfully printed using a lab-built bioprinter. Rapid scan EPR images reflective of the expected oxygen concentration levels have been acquired. An unreported problem of oxygen depletion in bioprinted constructs by the residual photoinitiator has been documented. EPR imaging is proposed as a control method for its removal. The oxygen consumption rates by HEK293T cells within a bioprinted cylinder have been imaged and quantified.ConclusionsThe feasibility of the cointegration of 4D EPR imaging and 4D bioprinting has been demonstrated. The proof-of-concept experiments, which were conducted using oxygen probes loaded into GelMA, lay the foundation for a broad range of applications, such as bioprinting with many types of bioinks loaded with diverse varieties of molecular spin probes.

Saving Oneself Through Labor: Disabled Workers and Social Welfare Production in Southwest China, 1956–65

Abstract This article examines the organization of social welfare production work (shehui fuli shengchan gongzuo) in China’s southwest Sichuan province from 1956 to 1965, with a focus on the marginalized experience of disabled workers during and after the Great Leap Forward Campaign (1958–62). Utilizing unexamined state archives, local gazetteers, and newspaper publications, the study traces how disabled workers were incorporated into or excluded from the campaign and their survival strategies after its derailment. During the Great Leap Forward, a campaign that aimed to rapidly industrialize China and accelerate developmental timelines, disabled workers were mobilized into collective production for the first time in the People’s Republic of China. When the industrial labor force needed to shrink, however, these once-mobilized disabled workers were marginalized and excluded from the state production system and instead resorted to heterodox forms of labor not officially recognized by the Communist state. The article argues that the tension between disabled workers and the Chinese Communist state, intensified by poor economic conditions, stemmed from the marginalization of disabled individuals with limited productivity in the state’s idealized vision of productive labor. By uncovering the interplay between disability, labor mobilization, and state ideology, this article contributes to a deeper understanding of the social and economic dynamics during the Great Leap Forward era.

Species-specific in situ hybridization confirms arrested development of Henneguya ictaluri in hybrid catfish (Channel Catfish × Blue Catfish) under experimental conditions, with notes on mixed-species infections in clinical cases of proliferative gill disease from Mississippi catfish aquaculture.

Proliferative gill disease (PGD) in Channel Catfish Ictalurus punctatus and hybrid catfish (Channel Catfish × Blue Catfish I. furcatus) is attributed to the myxozoan Henneguya ictaluri. Despite evidence of decreased H. ictaluri transmission and impaired parasite development in hybrid catfish, PGD still occurs in hybrid production systems. Previous metagenomic assessments of clinical PGD cases revealed numerous myxozoans within affected gill tissues in addition to H. ictaluri. The objective of this study was to investigate the development and pathologic contributions of H. ictaluri and other myxozoans in naturally and experimentally induced PGD. Henneguya species-specific in situ hybridization (ISH) assays were developed using RNAscope technology. Natural infections were sourced from diagnostic case submissions in 2019. Experimental challenges involved Channel Catfish and hybrid catfish exposed to pond water from an active PGD outbreak, and the fish were sampled at 1, 7, 10, 12, 14, 16, 18, and 20 weeks postchallenge. Nine unique ISH probes were designed, targeting a diagnostic variable region of the 18S ribosomal RNA gene of select myxozoan taxa identified in clinical PGD cases. Partial validation from pure H. ictaluri, H. adiposa, H. postexilis, and H. exilis infections illustrated species-specific labeling and no cross-reactivity between different myxozoan species or the catfish hosts. After experimental challenge, mature plasmodia of H. ictaluri and H. postexilis formed in Channel Catfish but were not observed in hybrids, suggesting impaired or delayed sporogenesis in the hybridized host. These investigations also confirmed the presence of mixed infections in clinical PGD cases. Although H. ictaluri appears to be the primary cause of PGD, presporogonic stages of other myxozoans were also present, which may contribute to disease pathology and exacerbate respiratory compromise by further altering normal gill morphology. This work provides molecular confirmation and more resolute developmental timelines of H. ictaluri and H. postexilis in Channel Catfish and supports previous research indicating impaired or precluded H. ictaluri sporogony in hybrid catfish.

Bilingual children display comparative strength using prosodic cues for pragmatic word learning

Aims/objectives/research questions: Previous studies indicate differences in the way children who grow up with two languages use socio-pragmatic cues to help them identify referents and learn new words, yet the nature of these differences (executive control, better attention to social cues, or pragmatic reasoning) has not been investigated. Design/methodology/approach: This study examined 270 monolingual and bilingually exposed 4–6-year-old children’s performance in 2 tasks using different prosodic cues (contrastive stress and emotional affect) for fast mapping. It avoids a design where children have to inhibit an irrelevant cue, which would enhance the role of differences in executive control. Data/analysis: We performed statistical analyses using a logistic regression mixed model. Findings/conclusions: The bilingually exposed group performed lower than monolinguals in a control condition involving structural language (0.83 vs. 0.92). However, they performed on par with monolinguals in a pragmatic condition when considering only semantically correct answers in both groups (0.55 vs. 0.58), and even displayed significant comparative strength in the task once control performance and demographic variables were taken into account. This effect appeared when the task required reasoning about the speaker’s communicative intentions (contrastive stress) but not when children merely had to recognise a communicative cue (emotional affect). Originality: No study has so far investigated the socio-pragmatic abilities of bilingual children using a task that did not require inhibiting an irrelevant cue. Implications: These findings have implications for bilingual education and a better understanding of the impact of being educated in two languages. We also draw attention to implications regarding the existence of different types of pragmatic skills which may have differing developmental timelines and rely on different sets of abilities.

A single cell genomics atlas of the Drosophila larval eye reveals distinct photoreceptor developmental timelines

The Drosophila eye is a powerful model system to study the dynamics of cell differentiation, cell state transitions, cell maturation, and pattern formation. However, a high-resolution single cell genomics resource that accurately profiles all major cell types of the larval eye disc and their spatiotemporal relationships is lacking. Here, we report transcriptomic and chromatin accessibility data for all known cell types in the developing eye. Photoreceptors appear as strands of cells that represent their dynamic developmental timelines. As photoreceptor subtypes mature, they appear to assume a common transcriptomic profile that is dominated by genes involved in axon function. We identify cell type maturation genes, enhancers, and potential regulators, as well as genes with distinct R3 or R4 photoreceptor specific expression. Finally, we observe that the chromatin accessibility between cones and photoreceptors is distinct. These single cell genomics atlases will greatly enhance the power of the Drosophila eye as a model system.

Exacerbated Zika virus-induced neuropathology and microcephaly in fetuses of dengue-immune nonhuman primates.

Zika virus (ZIKV) is a mosquito-borne flavivirus that can vertically transmit from mother to fetus, potentially causing congenital defects, including microcephaly. It is not fully understood why some fetuses experience severe complications after in utero exposure to ZIKV, whereas others do not. Given the antigenic similarity between ZIKV and the closely related virus dengue (DENV) and the potential of DENV-specific antibodies to enhance ZIKV disease severity in mice, we questioned whether maternal DENV immunity could influence fetal outcomes in a nonhuman primate model of ZIKV vertical transmission. We found significantly increased severity of congenital Zika syndrome (CZS) in fetuses of DENV-immune cynomolgus macaques infected with ZIKV in early pregnancy compared with naïve controls, which occurred despite no effect on maternal ZIKV infection or antibody responses. Ultrasound measurements of head circumference and biparietal diameter measurements taken sequentially throughout pregnancy demonstrated CZS in fetuses of DENV-immune pregnant macaques. Furthermore, severe CZS enhanced by DENV immunity was typified by reduced cortical thickness and increased frequency of neuronal death, hemorrhaging, cellular infiltrations, calcifications, and lissencephaly in fetal brains. This study shows that maternal immunity to DENV can worsen ZIKV neurological outcomes in fetal primates, and it provides an animal model of vertical transmission closely approximating human developmental timelines that could be used to investigate severe ZIKV disease outcomes and interventions in fetuses.

MEG correlates of speech planning in simple vs. interactive picture naming in children and adults.

The picture naming task is common both as a clinical task and as a method to study the neural bases of speech production in the healthy brain. However, this task is not reflective of most naturally occurring productions, which tend to happen within a context, typically in dialogue in response to someone else's production. How the brain basis of the classic "confrontation picture naming" task compares to the planning of utterances in dialogue is not known. Here we used magnetoencephalography (MEG) to measure neural activity associated with language production using the classic picture naming task as well as a minimal variant of the task, intended as more interactive or dialogue-like. We assessed how neural activity is affected by the interactive context in children, teenagers, and adults. The general pattern was that in adults, the interactive task elicited a robust sustained increase of activity in frontal and temporal cortices bilaterally, as compared to simple picture naming. This increase was present only in the left hemisphere in teenagers and was absent in children, who, in fact, showed the reverse effect. Thus our findings suggest a robustly bilateral neural basis for the coordination of interaction and a very slow developmental timeline for this network.