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The human neonatal cerebellum is one-fourth of its adult size yet contains the blueprint required to integrate environmental cues with developing motor, cognitive and emotional skills into adulthood. Although mature cerebellar neuroanatomy is well studied, understanding of its developmental origins is limited. In this study, we systematically mapped the molecular, cellular and spatial composition of human fetal cerebellum by combining laser capture microscopy and SPLiT-seq single-nucleus transcriptomics. We profiled functionally distinct regions and gene expression dynamics within cell types and across development. The resulting cell atlas demonstrates that the molecular organization of the cerebellar anlage recapitulates cytoarchitecturally distinct regions and developmentally transient cell types that are distinct from the mouse cerebellum. By mapping genes dominant for pediatric and adult neurological disorders onto our dataset, we identify relevant cell types underlying disease mechanisms. These data provide a resource for probing the cellular basis of human cerebellar development and disease. SPLiT-seq single-nucleus RNA sequencing of the developing human cerebellum reveals cell-type complexities and prolonged maturation compared to mouse with important disease implications.

Historically, the midbrain and hindbrain have been considered of secondary importance to the cerebrum, which has typically been acknowledged as the most important part of the brain. In the past, radiologists and pathologists did not regularly examine these structures—also known as the brainstem and cerebellum—because they are small and difficult to remove without damage. With recent developments in neuroimaging, neuropathology, and neurogenetics, many developmental disorders of the midbrain and hindbrain have emerged as causes of neurodevelopmental dysfunction. These research advances may change the way in which we treat these patients in the future and will enhance the clinical acumen of the practising neurologist and thereby improve the diagnosis and treatment of these patients.

We present histological and molecular analyses of the developing human cerebellum from 30 days after conception to 9 months after birth. Differences in developmental patterns between humans and mice include spatiotemporal expansion of both ventricular and rhombic lip primary progenitor zones to include subventricular zones containing basal progenitors. The human rhombic lip persists longer through cerebellar development than in the mouse and undergoes morphological changes to form a progenitor pool in the posterior lobule, which is not seen in other organisms, not even in the nonhuman primate the macaque. Disruptions in human rhombic lip development are associated with posterior cerebellar vermis hypoplasia and Dandy-Walker malformation. The presence of these species-specific neural progenitor populations refines our insight into human cerebellar developmental disorders.

Outbred laboratory mouse populations are widely used in biomedical research. Since little is known about the degree of genetic variation present in these populations, they are not widely used for genetic studies. Commercially available outbred CD-1 mice are drawn from an extremely large breeding population that has accumulated many recombination events, which is desirable for genome-wide association studies. We therefore examined the degree of genome-wide variation within CD-1 mice to investigate their suitability for genetic studies. The CD-1 mouse genome displays patterns of linkage disequilibrium and heterogeneity similar to wild-caught mice. Population substructure and phenotypic differences were observed among CD-1 mice obtained from different breeding facilities. Differences in genetic variation among CD-1 mice from distinct facilities were similar to genetic differences detected between closely related human populations, consistent with a founder effect. This first large-scale genetic analysis of the outbred CD-1 mouse strain provides important considerations for the design and analysis of genetic studies in CD-1 mice.

There has been significant advancement in various aspects of scientific knowledge concerning the role of cerebellum in the etiopathogenesis of autism. In the current consensus paper, we will observe the diversity of opinions regarding the involvement of this important site in the pathology of autism. Recent emergent findings in literature related to cerebellar involvement in autism are discussed, including: cerebellar pathology, cerebellar imaging and symptom expression in autism, cerebellar genetics, cerebellar immune function, oxidative stress and mitochondrial dysfunction, GABAergic and glutamatergic systems, cholinergic, dopaminergic, serotonergic, and oxytocin-related changes in autism, motor control and cognitive deficits, cerebellar coordination of movements and cognition, gene–environment interactions, therapeutics in autism, and relevant animal models of autism. Points of consensus include presence of abnormal cerebellar anatomy, abnormal neurotransmitter systems, oxidative stress, cerebellar motor and cognitive deficits, and neuroinflammation in subjects with autism. Undefined areas or areas requiring further investigation include lack of treatment options for core symptoms of autism, vermal hypoplasia, and other vermal abnormalities as a consistent feature of autism, mechanisms underlying cerebellar contributions to cognition, and unknown mechanisms underlying neuroinflammation.

Patients with cerebral small-vessel disease (CSVD) exhibit perturbed end-artery function and have an increased risk for stroke and age-related cognitive decline. Here, we used targeted genome-wide association (GWA) analysis and defined a CSVD locus adjacent to the forkhead transcription factor FOXC1. Moreover, we determined that the linked SNPs influence FOXC1 transcript levels and demonstrated that patients as young as 1 year of age with altered FOXC1 function exhibit CSVD. MRI analysis of patients with missense and nonsense mutations as well as FOXC1-encompassing segmental duplication and deletion revealed white matter hyperintensities, dilated perivascular spaces, and lacunar infarction. In a zebrafish model, overexpression or morpholino-induced suppression of foxc1 induced cerebral hemorrhage. Inhibition of foxc1 perturbed platelet-derived growth factor (Pdgf) signaling, impairing neural crest migration and the recruitment of mural cells, which are essential for vascular stability. GWA analysis also linked the FOXC1-interacting transcription factor PITX2 to CSVD, and both patients with PITX2 mutations and murine Pitx2-/- mutants displayed brain vascular phenotypes. Together, these results extend the genetic etiology of stroke and demonstrate an increasing developmental basis for human cerebrovascular disease.

The hippocampal dentate gyrus (DG) is a unique brain region maintaining neural stem cells (NCSs) and neurogenesis into adulthood. We used multiphoton imaging to visualize genetically defined progenitor subpopulations in live slices across key stages of mouse DG development, testing decades old static models of DG formation with molecular identification, genetic-lineage tracing, and mutant analyses. We found novel progenitor migrations, timings, dynamic cell-cell interactions, signaling activities, and routes underlie mosaic DG formation. Intermediate progenitors (IPs, Tbr2+) pioneered migrations, supporting and guiding later emigrating NSCs (Sox9+) through multiple transient zones prior to converging at the nascent outer adult niche in a dynamic settling process, generating all prenatal and postnatal granule neurons in defined spatiotemporal order. IPs (Dll1+) extensively targeted contacts to mitotic NSCs (Notch active), revealing a substrate for cell-cell contact support during migrations, a developmental feature maintained in adults. Mouse DG formation shares conserved features of human neocortical expansion.

Mutations in the catalytic subunit of phosphoinositide 3-kinase ( PIK3CA) and other PI3K-AKT pathway components have been associated with cancer and a wide spectrum of brain and body overgrowth. In the brain, the phenotypic spectrum of PIK3CA -related segmental overgrowth includes bilateral dysplastic megalencephaly, hemimegalencephaly and focal cortical dysplasia, the most common cause of intractable pediatric epilepsy. We generated mouse models expressing the most common activating Pik3ca mutations ( H1047R and E545K ) in developing neural progenitors. These accurately recapitulate all the key human pathological features including brain enlargement, cortical malformation, hydrocephalus and epilepsy, with phenotypic severity dependent on the mutant allele and its time of activation. Underlying mechanisms include increased proliferation, cell size and altered white matter. Notably, we demonstrate that acute 1 hr-suppression of PI3K signaling despite the ongoing presence of dysplasia has dramatic anti-epileptic benefit. Thus PI3K inhibitors offer a promising new avenue for effective anti-epileptic therapy for intractable pediatric epilepsy patients. An enzyme called PI3K is involved in a major signaling pathway that controls cell growth. Mutations in this pathway have devastating consequences. When such mutations happen in adults, they can lead to cancer. Mutations that occur in embryos can cause major developmental birth defects, including abnormally large brains. After birth, these developmental problems can cause intellectual disabilities, autism and epilepsy. Children with this kind of epilepsy often do not respond to currently available seizure medications. There are several outstanding questions that if answered could help efforts to develop treatments for children with brain growth disorders. Firstly, how do the developmental abnormalities happen? Do the abnormalities themselves cause epilepsy? And can drugs that target this pathway, and are already in clinical trials for cancer, control seizures? Now, Roy et al. have made mouse models of these human developmental brain disorders and used them to answer these questions. The mice were genetically engineered to have various mutations in the gene that encodes the catalytic subunit of the PI3K enzyme. The mutations were the same as those found in people with brain overgrowth disorders, and were activated only in the developing brain of the mice. These mutations caused enlarged brain size, fluid accumulation in the brain, brain malformations and epilepsy in developing mice – thus mimicking the human birth defects. The severity of these symptoms depended on the specific mutation and when the mutant genes were turned on during development. Next, Roy et al. studied these mice to see if the seizures could be treated using a drug, that has already been developed for brain cancer. This drug specifically targets and reduces the activity of PI3K. Adult mutant mice with brain malformations were treated for just one hour; this dramatically reduced their seizures. These experiments prove that seizures associated with this kind of brain overgrowth disorder are driven by ongoing abnormal PI3K activity and can be treated even when underlying brain abnormalities persist. Roy et al. suggest that drugs targeting PI3K might help treat seizures in children with these brain overgrowth disorders.

Model organism studies have demonstrated that cell fate specification decisions play an important role in normal brain development. Their role in human neurodevelopmental disorders, however, is poorly understood, with very few examples described. The cerebellum is an excellent system to study mechanisms of cell fate specification. Although signals from the isthmic organizer are known to specify cerebellar territory along the anterior–posterior axis of the neural tube, the mechanisms establishing the cerebellar anlage along the dorsal–ventral axis are unknown. Here we show that the gene encoding pancreatic transcription factor PTF1A, which is inactivated in human patients with cerebellar agenesis, is required to segregate the cerebellum from more ventral extracerebellar fates. Using genetic fate mapping in mice, we show that in the absence of Ptf1a , cells originating in the cerebellar ventricular zone initiate a more ventral brainstem expression program, including LIM homeobox transcription factor 1 beta and T-cell leukemia homeobox 3. Misspecified cells exit the cerebellar anlage and contribute to the adjacent brainstem or die, leading to cerebellar agenesis in Ptf1a mutants. Our data identify Ptf1a as the first gene involved in the segregation of the cerebellum from the more ventral brainstem. Further, we propose that cerebellar agenesis represents a new, dorsal-to-ventral, cell fate misspecification phenotype in humans.

The extent of neocortical gyrification is an important determinant of a species’ cognitive abilities, yet the mechanisms regulating cortical gyrification are poorly understood. We uncover long-range regulation of this process originating at the telencephalic dorsal midline, where levels of secreted Bmps are maintained by factors in both the neuroepithelium and the overlying mesenchyme. In the mouse, the combined loss of transcription factors Lmx1a and Lmx1b, selectively expressed in the midline neuroepithelium and the mesenchyme respectively, causes dorsal midline Bmp signaling to drop at early neural tube stages. This alters the spatial and temporal Wnt signaling profile of the dorsal midline cortical hem, which in turn causes gyrification of the distal neocortex. Our study uncovers early mesenchymal-neuroepithelial interactions that have long-range effects on neocortical gyrification and shows that lissencephaly in mice is actively maintained via redundant genetic regulation of dorsal midline development and signaling. The contribution of long-range signaling to cortical gyrification remains poorly understood. In this study, authors demonstrate that the combined genetic loss of transcription factors Lmx1a and Lmx1b, expressed in the telencephalic dorsal midline neuroepithelium and head mesenchyme, respectively, induces gyrification in the mouse neocortex