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The autosomal dominant disorder tuberous sclerosis complex (TSC) is characterized by an array of manifestations both within and outside of the central nervous system (CNS), including hamartomas and other malformations. TSC is caused by mutations in the TSC1 or TSC2 gene resulting in activation of the mechanistic target of rapamycin (mTOR) signaling pathway. Study of TSC has shed light on the critical role of the mTOR pathway in neurodevelopment. This update reviews the genetic basis of TSC, its cardinal phenotypic CNS features, and recent developments in the field of TSC and other mTOR-altered disorders.

As the brain develops, neurons migrate from zones of proliferation to their final locations, where they begin to build circuits. Paredes et al. have discovered that shortly after birth, a group of neurons that proliferates near the ventricles migrates in chains alongside circulatory vessels into the frontal lobes (see the Perspective by McKenzie and Fishell). Young neurons that migrate postnatally into the anterior cingulate cortex then develop features of inhibitory interneurons. The number of migratory cells decreases over the first 7 months of life, and by 2 years of age, migratory cells are not evident. Any damage during migration, such as hypoxia, may affect the child's subsequent physical and behavioral development. Science , this issue p. 81 ; see also p. 38 Neurons are still finding their places as inhibitory circuits are established in the developing postnatal brain. [Also see Perspective by McKenzie ] The first few months after birth, when a child begins to interact with the environment, are critical to human brain development. The human frontal lobe is important for social behavior and executive function; it has increased in size and complexity relative to other species, but the processes that have contributed to this expansion are unknown. Our studies of postmortem infant human brains revealed a collection of neurons that migrate and integrate widely into the frontal lobe during infancy. Chains of young neurons move tangentially close to the walls of the lateral ventricles and along blood vessels. These cells then individually disperse long distances to reach cortical tissue, where they differentiate and contribute to inhibitory circuits. Late-arriving interneurons could contribute to developmental plasticity, and the disruption of their postnatal migration or differentiation may underlie neurodevelopmental disorders.

We designed a liquid biopsy (LB) platform employing low-pass whole genome sequencing (LP-WGS) and targeted sequencing of cell-free (cf) DNA from plasma to detect genome-wide copy number alterations (CNAs) and gene fusions in pediatric solid tumors. A total of 143 plasma samples were analyzed from 19 controls and 73 patients, including 44 bone or soft-tissue sarcomas and 12 renal, 10 germ cell, five hepatic, and two thyroid tumors. cfDNA was isolated from plasma collected at diagnosis, during and after therapy, and/or at relapse. Twenty-six of 37 (70%) patients enrolled at diagnosis without prior therapy (radiation, surgery, or chemotherapy) had circulating tumor DNA (ctDNA), based on the detection of CNAs from LP-WGS, including 18 of 27 (67%) patients with localized disease and eight of 10 (80%) patients with metastatic disease. None of the controls had detectable somatic CNAs. There was a high concordance of CNAs identified by LP-WGS to CNAs detected by chromosomal microarray analysis in the matching tumors. Mutations identified in tumor samples with our next-generation sequencing (NGS) panel, OncoKids®, were also detected by LP-WGS of ctDNA in 14 of 26 plasma samples. Finally, we developed a hybridization-based capture panel to target EWSR1 and FOXO1 fusions from patients with Ewing sarcoma or alveolar rhabdomyosarcoma (ARMS), respectively. Fusions were detected in the plasma from 10 of 12 patients with Ewing sarcoma and in two of two patients with ARMS. Combined, these data demonstrate the clinical applicability of our LB platform to evaluate pediatric patients with a variety of solid tumors.

Plants utilize variation in day length (photoperiod) to anticipate seasonal changes. They respond by modulating their growth and development to maximize seed production, which in cereal crops is directly related to yield. In wheat (Triticum aestivum), the acceleration of flowering under long days (LD) is dependent on the light induction of PHOTOPERIOD1 (PPD1) by phytochromes. Under LD, PPD1 activates FLOWERING LOCUS T1 (FT1), a mobile signaling protein that travels from the leaves to the shoot apical meristem to promote flowering. Here, we show that the interruption of long nights by short pulses of light (\"night-break\" [NB]) accelerates wheat flowering, suggesting that the duration of the night is critical for wheat photoperiodic response. PPD1 transcription was rapidly upregulated by NBs, and the magnitude of this induction increased with the length of darkness preceding the NB. Cycloheximide abolished the NB up-regulation of PPD1, suggesting that this process is dependent on active protein synthesis during darkness. While one NB was sufficient to induce PPD1, more than 15 NBs were required to induce high levels of FT1 expression and a strong acceleration of flowering. Multiple NBs did not affect the expression of core circadian clock genes. The acceleration of flowering by NB disappeared in ppd1-null mutants, demonstrating that this response is mediated by PPD1. The acceleration of flowering was strongest when NBs were applied in the middle of the night, suggesting that in addition to PPD1, other circadian-controlled factors are required for the up-regulation of FT1 expression and the acceleration of flowering.

This study evaluates the diagnostic utility of OLIG2 immunohistochemistry for distinguishing between pediatric high-grade gliomas (pHGG) and embryonal tumors (ETs) of the CNS. Utilizing a retrospective pediatric cohort (1990-2021) of 56 CNS tumors, classified initially as primitive neuroectodermal tumors or CNS ET, we reclassified the cases based on WHO CNS5 criteria after comprehensive review and additional molecular testing that included next-generation sequencing and DNA methylation profiling. Our results indicate that OLIG2 immunopositivity was negative or minimal in a significant subset of pHGG cases (6 out of 11). At the same time, it showed diffuse expression in all cases of CNS neuroblastomas with FOXR2 activation (5/5), demonstrating its limited specificity in differentiating between pHGG and ET. Variable OLIG2 expression in other ETs, ATRT, and ETMR suggests the broader diagnostic implications of the marker. Furthermore, incidental findings of OLIG2 positivity in cases traditionally expected to be negative, such as medulloblastoma and ependymoma, introduce an additional layer of complexity. Together, these findings highlight the challenges of relying solely on OLIG2 immunostaining for accurate tumor classification in pediatric CNS neoplasms and underscore the importance of an integrated diagnostic approach.

Many genes that drive normal cellular development also contribute to oncogenesis. Medulloblastoma (MB) tumors likely arise from neuronal progenitors in the cerebellum, and we hypothesized that the heterogeneity observed in MBs with sonic hedgehog (SHH) activation could be due to differences in developmental pathways. To investigate this question, here we perform single-nucleus RNA sequencing on highly differentiated SHH MBs with extensively nodular histology and observed malignant cells resembling each stage of canonical granule neuron development. Through innovative computational approaches, we connect these results to published datasets and find that some established molecular subtypes of SHH MB appear arrested at different developmental stages. Additionally, using multiplexed proteomic imaging and MALDI imaging mass spectrometry, we identify distinct histological and metabolic profiles for highly differentiated tumors. Our approaches are applicable to understanding the interplay between heterogeneity and differentiation in other cancers and can provide important insights for the design of targeted therapies. The role of developmental pathways in medulloblastoma tumours (MB) with sonic hedgehog (SHH) activation remains to be explored. Here, the authors perform multi-omic analysis and characterise the key transcriptomic and metabolic patterns of highly differentiated cells in SHH MBs.

DICER1 syndrome is a hereditary cancer predisposition syndrome caused by deleterious germline DICER1 mutations. Characteristic “hotspot” somatic mutations of DICER1 have been identified in DICER1 -associated tumors. With the exception of genitourinary embryonal rhabdomyosarcoma and anaplastic sarcoma of the kidney, sarcomas are rarely reported in DICER1 syndrome. Herein, we report the clinical, histopathologic, and molecular findings of a germline DICER1 -associated ovarian sarcoma in a 5-year-old female, a somatic DICER1 -associated metastatic peritoneal sarcoma in a 16-year-old female, and a somatic DICER1 -associated primary intracranial sarcoma in a 4-year-old male. A comprehensive review of the literature, including 83 DICER1 -associated sarcomas, illustrates an unequivocal histologic pattern mimicking pleuropulmonary blastoma, regardless of the site of origin. The features include undifferentiated small round blue cells, poorly differentiated spindle cells, and large bizarre pleomorphic cells (anaplasia), often with rhabdomyoblastic and/or chondroid differentiation, and rare bone/osteoid formation. This unique heterogeneous histologic pattern should raise suspicion for pathogenic DICER1 mutation(s) warranting a detailed review of the family history and DICER1 mutation analysis. In addition to expanding the phenotypic spectrum of DICER1 -associated conditions, identification of pathogenic DICER1 variants facilitates optimized genetic counseling, caregiver education and judicious imaging-based surveillance.

Alternative routes of administration are one approach that could be used to bypass the blood–brain barrier (BBB) for effective drug delivery to the central nervous system (CNS). Here, we focused on intranasal delivery of polymer nanoparticles. We hypothesized that surface modification of poly(lactic-co-glycolic acid) (PLGA) nanoparticles with rabies virus glycoprotein (RVG29) would increase residence time and exposure of encapsulated payload to the CNS compared to non-targeted nanoparticles. Delivery kinetics and biodistribution were analyzed by administering nanoparticles loaded with the carbocyanine dye 1,1′-Dioctadecyl-3,3,3′,3′-Tetramethylindotricarbocyanine Iodide (DiR) to healthy mice. Intranasal administration yielded minimal exposure of nanoparticle payload to most peripheral organs and rapid, effective delivery to whole brain. Regional analysis of payload delivery within the CNS revealed higher delivery to tissues closest to the trigeminal nerve, including the olfactory bulb, striatum, midbrain, brainstem, and cervical spinal cord. RVG29 surface modifications presented modest targeting benefits to the striatum, midbrain, and brainstem 2 h after administration, although targeting was not observed 30 min or 6 h after administration. Payload delivery to the trigeminal nerve was 3.5× higher for targeted nanoparticles compared to control nanoparticles 2 h after nanoparticle administration. These data support a nose-to-brain mechanism of drug delivery that closely implicates the trigeminal nerve for payload delivery from nanoparticles via transport of intact nanoparticles and eventual diffusion of payload. Olfactory and CSF routes are also observed to play a role. These data advance the utility of targeted nanoparticles for nose-to-brain drug delivery of lipophilic payloads and provide mechanistic insight to engineer effective delivery vectors to treat disease in the CNS.

Atypical teratoid/rhabdoid tumor (AT/RT) is a highly malignant tumor that may not only contain rhabdoid tumor cells but also poorly differentiated small‐round‐blue cells as well as areas with mesenchymal or epithelial differentiation. Little is known on factors associated with histopathological diversity. Recent studies demonstrated three molecular subgroups of AT/RT, namely ATRT‐TYR, ATRT‐SHH, and ATRT‐MYC. We thus aimed to investigate if morphological patterns might be related to molecular subgroup status. Hematoxylin‐eosin stained sections of 114 AT/RT with known molecular subgroup status were digitalized and independently categorized by nine blinded observers into four morphological categories, that is, “rhabdoid,” “small‐round‐blue,” “epithelial,” and “mesenchymal.” The series comprised 48 ATRT‐SHH, 40 ATRT‐TYR, and 26 ATRT‐MYC tumors. Inter‐observer agreement was moderate but significant (Fleiss’ kappa = 0.47; 95% C.I. 0.41‐0.53; p < 0.001) and there was a highly significant overall association between morphological categories and molecular subgroups for each of the nine observers (p < 0.0001). Specifically, the category “epithelial” was found to be over‐represented in ATRT‐TYR (p < 0.000001) and the category “small‐round‐blue” to be over‐represented in ATRT‐SHH (p < 0.01). The majority of ATRT‐MYC was categorized as “mesenchymal” or “rhabdoid,” but this association was less compelling. The specificity of the category “epithelial” for ATRT‐TYR was highest and accounted for 97% (range: 88‐99%) whereas sensitivity was low [49% (range: 35%–63%)]. In line with these findings, cytokeratin‐positivity was highly overrepresented in ATRT‐TYR. In conclusion, morphological features of AT/RT might reflect molecular alterations and may also provide a first hint on molecular subgroup status, which will need to be confirmed by DNA methylation profiling.