Defects In Brain Development Research Articles

Novel KIF26A variants associated with pediatric intestinal pseudo‐obstruction (PIPO) and brain developmental defects

AbstractPediatric intestinal pseudo‐obstruction (PIPO) is a rare congenital disorder of the enteric nervous system with distal colon aganglionosis potentially leading to intestinal obstruction. Recently, biallelic variants in KIF26A, encoding a crucial motor protein for the migration and differentiation of enteric neural crest cells, have been associated with a neurodevelopmental condition featuring cortical defects and PIPO‐like features, though in absence of aganglionosis. So far, only 10 patients have been reported. In this study, we investigated three subjects with congenital hydrocephalus, neurodevelopmental impairment, and intestinal obstruction megacolon syndrome. Brain MRI revealed malformations within cortical dysplasia spectrum, including polymicrogyria and heterotopia. Pathology study of the intestine revealed aganglionosis and elevated acetylcholinesterase activity in parasympathetic nerve fibers. Through trio‐exome sequencing (ES), we detected four novel biallelic KIF26A variants, including two missense changes (#1) and two distinct homozygous truncating variants in (#2 and #3). All variants are rare and predicted to be deleterious according to in silico tools. To characterize the impact of the missense variants, we performed 3D protein modeling using Alphafold3 and YASARA. Mutants exhibited increased energy scores compared to wild‐type protein, supporting a significant structural destabilization of the protein. Our study expands the genotype and phenotype spectrum of the emerging KIF26A‐related disorder.

Zika virus NS3 drives the assembly of a viroplasm-like structure.

Zika virus (ZIKV) is a mosquito-transmitted flavivirus that caused an epidemic in 2015-2016 in the Americas and raised serious global health concerns due to its association with congenital brain developmental defects in infected pregnancies. Upon infection, ZIKV assembles virus particles in a virus-generated toroidal compartment next to the nucleus called the replication factory, or viroplasm, which forms by remodeling the host cell endoplasmic reticulum (ER). How the viral proteins control viroplasm assembly remains unknown. Here we show that the ZIKV non-structural protein 3 (NS3) is sufficient to drive the assembly of a viroplasm-like structure (VLS) in human cells. NS3 encodes a dual-function protease and RNA helicase. The VLS is similar to the ZIKV viroplasm in its assembly near centrosomes at the nuclear periphery, its deformation of the nuclear membrane, its recruitment of ER, Golgi, and dsRNA, and its association with microtubules at its surface. While sufficient to generate a VLS, NS3 is less efficient in several aspects compared to viroplasm formation upon ZIKV infection. We further show that the helicase domain and not the protease domain is required for optimal VLS assembly and dsRNA recruitment. Overall, this work advances our understanding of the mechanism of viroplasm assembly by ZIKV and likely will extend to other flaviviruses.

Embryonic Lethal Phenotyping to Identify Candidate Genes Related with Birth Defects.

Congenital birth defects contribute significantly to preterm birth, stillbirth, perinatal death, infant mortality, and adult disability. As a first step to exploring the mechanisms underlying this major clinical challenge, we analyzed the embryonic phenotypes of lethal strains generated by random mutagenesis. In this study, we report the gross embryonic and perinatal phenotypes of 55 lethal strains randomly picked from a collection of mutants that carry piggyBac (PB) transposon inserts. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses suggested most of the analyzed mutations hit genes involved in heart and nervous development, or in Notch and Wnt signaling. Among them, 12 loci are known to be associated with human diseases. We confirmed 53 strains as embryonic or perinatal lethal, while others were subviable. Gross morphological phenotypes such as body size abnormality (29/55, 52.73%), growth or developmental delay (35/55, 63.64%), brain defects (9/55, 16.36%), vascular/heart development (31/55, 56.36%), and other structural defects (9/55, 16.36%) could be easily observed in the mutants, while three strains showed phenotypes similar to those of human patients. Furthermore, we detected body weight or body composition alterations in the heterozygotes of eight strains. One of them was the TGF-β signaling gene Smad2. The heterozygotes showed increased energy expenditure and a lower fat-to-body weight ratio compared to wild-type mice. This study provided new insights into mammalian embryonic development and will help understand the pathology of congenital birth defects in humans. In addition, it expanded our understanding of the etiology of obesity.

New Pharmacological Therapies in the Treatment of Epilepsy in the Pediatric Population.

Epilepsy is a disorder characterized by abnormal brain neuron activity, predisposing individuals to seizures. The International League Against Epilepsy (ILAE) categorizes epilepsy into the following groups: focal, generalized, generalized and focal, and unknown. Infants are the most vulnerable pediatric group to the condition, with the cause of epilepsy development being attributed to congenital brain developmental defects, white matter damage, intraventricular hemorrhage, perinatal hypoxic-ischemic injury, perinatal stroke, or genetic factors such as mutations in the Sodium Channel Protein Type 1 Subunit Alpha (SCN1A) gene. Due to the risks associated with this condition, we have investigated how the latest pharmacological treatments for epilepsy in children impact the reduction or complete elimination of seizures. We reviewed literature from 2018 to 2024, focusing on the age group from 1 month to 18 years old, with some studies including this age group as well as older individuals. The significance of this review is to present and compile research findings on the latest antiseizure drugs (ASDs), their effectiveness, dosing, and adverse effects in the pediatric population, which can contribute to selecting the best drug for a particular patient. The medications described in this review have shown significant efficacy and safety in the studied patient group, outweighing the observed adverse effects. The main aim of this review is to provide a comprehensive summary of the current state of knowledge regarding the newest pharmacotherapy for childhood epilepsy.

Unraveling the mechanistic interplay of mediators orchestrating the neuroprotective potential of harmine.

Neurodegenerative diseases (NDDs) encompass a range of conditions characterized by the specific dysfunction and continual decline of neurons, glial cells, and neural networks within the brain and spinal cord. The majority of NDDs exhibit similar underlying causes, including oxidative stress, neuroinflammation, and malfunctioning of mitochondria. Elevated levels of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), alongside decreased expression of brain-derived neurotrophic factor (BDNF) and glutamate transporter subtype 1 (GLT-1), constitute significant factors contributing to the pathogenesis of NDDs. Additionally, the dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) gene has emerged as a significant target for the treatment of NDDs at the preclinical level. It significantly contributes to developmental brain defects, early onset neurodegeneration, neuronal loss, and dementia in Down syndrome. Moreover, an impaired ubiquitin-proteosome system (UPS) also plays a pathological role in NDDs. Malfunctioning of UPS leads to abnormal protein buildup or aggregation of α-synuclein. α-Synuclein is a highly soluble unfolded protein that accumulates in Lewy bodies and Lewy neurites in Parkinson's disease and other synucleinopathies. Recent research highlights the promising potential of natural products in combating NDDs relative to conventional therapies. Alkaloids have emerged as promising candidates in the fight against NDDs. Harmine is a tricyclic β-carboline alkaloid (harmala alkaloid) with one indole nucleus and a six-membered pyrrole ring. It is extracted from Banisteria caapi and Peganum harmala L. and exhibits diverse pharmacological properties, encompassing neuroprotective, antioxidant, anti-inflammatory, antidepressant, etc. Harmine has been reported to mediate its neuroprotective via reducing the level of inflammatory mediators, NADPH oxidase, AChE, BChE and reactive oxygen species (ROS). Whereas, it has been observed to increase the levels of BDNF, GLT-1 and anti-oxidant enzymes, along with protein kinase-A (PKA)-mediated UPS activation. This review aims to discuss the mechanistic interplay of various mediators involved in the neuroprotective effect of harmine.

Potential Role of Protein Kinase FAM20C on the Brain in Raine Syndrome, an In Silico Analysis.

FAM20C (family with sequence similarity 20, member C) is a serine/threonine-specific protein kinase that is ubiquitously expressed and mainly associated with biomineralization and phosphatemia regulation. It is mostly known due to pathogenic variants causing its deficiency, which results in Raine syndrome (RNS), a sclerosing bone dysplasia with hypophosphatemia. The phenotype is recognized by the skeletal features, which are related to hypophosphorylation of different FAM20C bone-target proteins. However, FAM20C has many targets, including brain proteins and the cerebrospinal fluid phosphoproteome. Individuals with RNS can have developmental delay, intellectual disability, seizures, and structural brain defects, but little is known about FAM20C brain-target-protein dysregulation or about a potential pathogenesis associated with neurologic features. In order to identify the potential FAM20C actions on the brain, an in silico analysis was conducted. Structural and functional defects reported in RNS were described; FAM20C targets and interactors were identified, including their brain expression. Gene ontology of molecular processes, function, and components was completed for these targets, as well as for potential involved signaling pathways and diseases. The BioGRID and Human Protein Atlas databases, the Gorilla tool, and the PANTHER and DisGeNET databases were used. Results show that genes with high expression in the brain are involved in cholesterol and lipoprotein processes, plus axo-dendritic transport and the neuron part. These results could highlight some proteins involved in the neurologic pathogenesis of RNS.

Early-onset brain alterations during postnatal development in a mouse model of CDKL5 deficiency disorder

Mutations in the CDKL5 gene are the cause of CDKL5 deficiency disorder (CDD), a rare and severe neurodevelopmental condition characterized by early-onset epilepsy, motor impairment, intellectual disability, and autistic features. A mouse model of CDD, the Cdkl5 KO mouse, that recapitulates several aspects of CDD symptomology, has helped to highlight brain alterations leading to CDD neurological defects. Studies of brain morphogenesis in adult Cdkl5 KO mice showed defects in dendritic arborization of pyramidal neurons and in synaptic connectivity, a hypocellularity of the hippocampal dentate gyrus, and a generalized microglia over-activation. Nevertheless, no studies are available regarding the presence of these brain alterations in Cdkl5 KO pups, and their severity in early stages of life compared to adulthood. A deeper understanding of the CDKL5 deficient brain during an early phase of postnatal development would represent an important milestone for further validation of the CDD mouse model, and for the identification of the optimum time window for treatments that target defects in brain development. In sight of this, we comparatively evaluated the dendritic arborization and spines of cortical pyramidal neurons, cortical excitatory and inhibitory connectivity, microglia activation, and proliferation and survival of granule cells of the hippocampal dentate gyrus in hemizygous Cdkl5 KO male (−/Y) mice aged 7, 14, 21, and 60 days. We found that most of the structural alterations in Cdkl5 −/Y brains are already present in pups aged 7 days and do not worsen with age. In contrast, the difference in the density of excitatory and inhibitory terminals between Cdkl5 −/Y and wild-type mice changes with age, suggesting an age-dependent cortical excitatory/inhibitory synaptic imbalance. Confirming the precocious presence of brain defects, Cdkl5 −/Y pups are characterized by an impairment in neonatal sensory-motor reflexes.

The NuRD Complex in Neurodevelopment and Disease: A Case of Sliding Doors.

The Nucleosome Remodelling and Deacetylase (NuRD) complex represents one of the major chromatin remodelling complexes in mammalian cells, uniquely coupling the ability to "open" the chromatin by inducing nucleosome sliding with histone deacetylase activity. At the core of the NuRD complex are a family of ATPases named CHDs that utilise the energy produced by the hydrolysis of the ATP to induce chromatin structural changes. Recent studies have highlighted the prominent role played by the NuRD in regulating gene expression during brain development and in maintaining neuronal circuitry in the adult cerebellum. Importantly, components of the NuRD complex have been found to carry mutations that profoundly affect neurological and cognitive development in humans. Here, we discuss recent literature concerning the molecular structure of NuRD complexes and how the subunit composition and numerous permutations greatly determine their functions in the nervous system. We will also discuss the role of the CHD family members in an array of neurodevelopmental disorders. Special emphasis will be given to the mechanisms that regulate the NuRD complex composition and assembly in the cortex and how subtle mutations may result in profound defects of brain development and the adult nervous system.

Insights on the Role of α- and β-Tubulin Isotypes in Early Brain Development

Tubulins are the highly conserved subunit of microtubules which involve in various fundamental functions including brain development. Microtubules help in neuronal proliferation, migration, differentiation, cargo transport along the axons, synapse formation, and many more. Tubulin gene family consisting of multiple isotypes, their differential expression and varied post translational modifications create a whole new level of complexity and diversity in accomplishing manifold neuronal functions. The studies on the relation between tubulin genes and brain development opened a new avenue to understand the role of each tubulin isotype in neurodevelopment. Mutations in tubulin genes are reported to cause brain development defects especially cortical malformations, referred as tubulinopathies. There is an increased need to understand the molecular correlation between various tubulin mutations and the associated brain pathology. Recently, mutations in tubulin isotypes (TUBA1A, TUBB, TUBB1, TUBB2A, TUBB2B, TUBB3, and TUBG1) have been linked to cause various neurodevelopmental defects like lissencephaly, microcephaly, cortical dysplasia, polymicrogyria, schizencephaly, subcortical band heterotopia, periventricular heterotopia, corpus callosum agenesis, and cerebellar hypoplasia. This review summarizes on the microtubule dynamics, their role in neurodevelopment, tubulin isotypes, post translational modifications, and the role of tubulin mutations in causing specific neurodevelopmental defects. A comprehensive list containing all the reported tubulin pathogenic variants associated with brain developmental defects has been prepared to give a bird's eye view on the broad range of tubulin functions.

Role of Nesprin-2 and RanBP2 in BICD2-associated brain developmental disorders.

Bicaudal D2 (BICD2) is responsible for recruiting cytoplasmic dynein to diverse forms of subcellular cargo for their intracellular transport. Mutations in the human BICD2 gene have been found to cause an autosomal dominant form of spinal muscular atrophy (SMA-LED2), and brain developmental defects. Whether and how the latter mutations are related to roles we and others have identified for BICD2 in brain development remains little understood. BICD2 interacts with the nucleoporin RanBP2 to recruit dynein to the nuclear envelope (NE) of Radial Glial Progenitor cells (RGPs) to mediate their well-known but mysterious cell-cycle-regulated interkinetic nuclear migration (INM) behavior, and their subsequent differentiation to form cortical neurons. We more recently found that BICD2 also mediates NE dynein recruitment in migrating post-mitotic neurons, though via a different interactor, Nesprin-2. Here, we report that Nesprin-2 and RanBP2 compete for BICD2-binding in vitro. To test the physiological implications of this behavior, we examined the effects of known BICD2 mutations using in vitro biochemical and in vivo electroporation-mediated brain developmental assays. We find a clear relationship between the ability of BICD2 to bind RanBP2 vs. Nesprin-2 in controlling of nuclear migration and neuronal migration behavior. We propose that mutually exclusive RanBP2-BICD2 vs. Nesprin-2-BICD2 interactions at the NE play successive, critical roles in INM behavior in RGPs and in post-mitotic neuronal migration and errors in these processes contribute to specific human brain malformations.

Dynamics of TUBB protein with five majorly occurring natural variants: a risk of cortical dysplasia

Beta-tubulin (TUBB) protein is one of the components of the microtubule cytoskeleton that plays a critical role in the central nervous system. Genetic variants of TUBB cause cortical dysplasia, a developmental brain defect implicated in axonal guidance and the neuron migration. In this study, we assess pathogenic variants (Q15K, Y222F, M299V, V353I, and E401K) of TUBB protein and compared with non-pathogenic variant G235S to determine their impact on protein dynamic to cause cortical dysplasia. Among the analyzed variants, Q15K, Y222F, M299V, and E401K were noticed to have deleterious effect. Then, variant structures were modeled and their affinity with their known cofactor Guanosine-5'-triphosphate (GTP) was assessed which showed diverse binding energies ranged between (-7.436 to -6.950kcal/mol) for the variants compared to wild-type (-7.428kcal/mol). Finally, the molecular dynamics simulation of each variant was investigated which showed difference in trajectory between the pathogenic and non-pathogenic variant. Our analysis suggests change in amino acid residue of TUBB structure has notably affects the protein flexibility and their interactions with known cofactor. Overall, our findings provide insight on the relationship between TUBB variants and their structural dynamics that may cause diverse effects leading to cortical dysplasia.

Cystatin B deficiency results in sustained histone H3 tail cleavage in postnatal mouse brain mediated by increased chromatin-associated cathepsin L activity.

Cystatin B (CSTB) is a cysteine cathepsin inhibitor whose biallelic loss-of-function mutations in human result in defects in brain development and in neurodegeneration. The physiological function of CSTB is largely unknown, and the mechanisms underlying the human brain diseases remain poorly understood. We previously showed that CSTB modulates the proteolysis of the N-terminal tail of histone H3 (H3cs1) during in vitro neurogenesis. Here we investigated the significance of this mechanism in postnatal mouse brain. Spatiotemporal analysis of H3cs1 intensity showed that while H3cs1 in wild-type (wt) mice was found at varying levels during the first postnatal month, it was virtually absent in adult brain. We further showed that the high level of H3cs1 coincides with chromatin association of de novo synthesized cathepsin L suggesting a role for nuclear cathepsin L in brain development and maturation. On the contrary, the brains of Cstb -/- mice showed sustained H3cs1 proteolysis to adulthood with increased chromatin-associated cathepsin L activity, implying that CSTB regulates chromatin-associated cathepsin L activity in the postnatal mouse brain. As H3 tail proteolysis has been linked to cellular senescence in vitro, we explored the presence of several cellular senescence markers in the maturing Cstb -/- cerebellum, where we see increased levels of H3cs1. While several markers showed alterations in Cstb -/- mice, the results remained inconclusive regarding the association of deficient CSTB function with H3cs1-induced senescence. Together, we identify a molecular role for CSTB in brain with implications for brain development and disease.

Modeling maternal cholesterol exposure reveals a reduction of neural progenitor proliferation using human cerebral organoids

Abstract Maternal obesity raises the risk of high-cholesterol exposure for their offspring. Studies in cohorts and animal models report that maternal obesity could increase the risk of neurodevelopmental disorders in offspring including intellectual disabilities and autism spectrum disorders (ASDs). However, whether exposure to high cholesterol is responsible for brain developmental defects, as well as its underlying mechanism, is still unclear. Here, we constructed a cholesterol exposure model utilizing human pluripotent stem cell (hPSC)-derived cerebral organoids by exogenously adding cholesterol into the culture system. We observed enlargement of endosomes, decreased neural progenitor proliferation, and premature neural differentiation in brain organoids with the treatment of cholesterol. Moreover, in comparison with published transcriptome data, we found that our single-cell sequencing results showed a high correlation with ASD, indicating that high cholesterol during maternal might mediate the increased risk of ASD in the offspring. Our results reveal a reduction of neural progenitor proliferation in a cholesterol exposure model, which might be a promising indicator for prenatal diagnosis and offer a dynamic human model for maternal environment exposure.

Deficiency of Murine UFM1-Specific E3 Ligase Causes Microcephaly and Inflammation.

The UFM1 conjugation system is a Ubiquitin (Ub)-like modification system that is essential for animal development and normal physiology of multiple tissues and organs. It consists of UFM1, a Ub-like modifier, and the UFM1-specific enzymes (namely E1 enzyme UBA5, E2 enzyme UFC1 E2, and E3 ligases) that catalyze conjugation of UFM1 to its specific protein targets. Clinical studies have identified rare genetic variants in human UFM1, UBA5 and UFC1 genes that were linked to early-onset encephalopathy and defective brain development, strongly suggesting the critical role of the UFM1 system in the nervous system. Yet, the physiological function of this system in adult brain remains not defined. In this study, we investigated the role of UFM1 E3 ligase in adult mouse and found that both UFL1 and UFBP1 proteins, two components of UFM1 E3 ligase, are essential for survival of mature neurons in adult mouse. Neuron-specific deletion of either UFL1 or UFBP1 led to significant neuronal loss and elevation of inflammatory response. Interestingly, loss of one allele of UFBP1 genes caused the occurrence of seizure-like events. Our study has provided genetic evidence for the indispensable role of UFM1 E3 ligase in mature neurons and further demonstrated the importance of the UFM1 system in the nervous system.

Missense variant c.1460 T > C (p.L487P) enhances protein degradation of ER mannosyltransferase ALG9 in two new ALG9-CDG patients presenting with West syndrome and review of the literature.

ALG9-CDG is a CDG-I defect within the group of Congenital Disorders of Glycosylation (CDG). We here describe the clinical symptoms of two new and unrelated ALG9-CDG patients, both carrying the novel homozygous missense variant c.1460 T > C (p.L487P) in the ALG9 gene which led to global developmental delay, psychomotor disability, facial dysmorphisms, brain and heart defects, hearing loss, hypotonia, as well as feeding problems. New clinical symptoms comprised West syndrome with hypsarrhythmia. Quantitative RT-PCR analysis revealed a significantly enhanced ALG9 mRNA transcript level, whereas the protein amount in fibroblasts was significantly reduced. This could be ascribed to a stronger degradation of the mutated ALG9 protein in patient fibroblasts. Lipid-linked oligosaccharide analysis showed an ALG9-CDG characteristic accumulation of Man6GlcNAc2-PP-dolichol and Man8GlcNAc2-PP-dolichol in patient cells. The clinical findings of our patients and of all previously published ALG9-CDG patients are brought together to further expand the knowledge about this rare N-glycosylation disorder. SYNOPSIS: Homozygosity for p.L487P in ALG9 causes protein degradation and leads to West syndrome.

Pathogenic Infections during Pregnancy and the Consequences for Fetal Brain Development.

Pathogens comprised of viruses, bacteria, gut microbiome, and parasites are a leading cause of ever-emerging diseases in humans. Studying pathogens for their ability to cause diseases is a topic of critical discussion among scientists and pharmaceutical centers for effective drug development that diagnose, treat, and prevent infection-associated disorders. Pathogens impact health either directly by invading the host or by eliciting an acute inflammatory immune response. This paradigm of inflammatory immune responses is even more consequential in people who may be immunocompromised. In this regard, pregnancy offers an altered immunity scenario, which may allow the onset of severe diseases. Viruses, such as Influenza, HIV, and now SARS-CoV-2, associated with the COVID-19 pandemic, raise new concerns for maternal and fetal/neonatal health. Intrauterine bacterial and parasitic infections are also known to impact pregnancy outcomes and neonatal health. More importantly, viral and bacterial infections during pregnancy have been identified as a common contributor to fetal brain development defects. Infection-mediated inflammatory uterine immune milieu is thought to be the main trigger for causing poor fetal brain development, resulting in long-term cognitive impairments. The concept of in utero programming of childhood and adult disorders has revolutionized the field of neurodevelopment and its associated complications. Recent findings in mice and humans clearly support the idea that uterine immunity during pregnancy controls the health trajectory of the child and considerably influences the cognitive function and mental health. In this review, we focus on the in utero programming of autism spectrum disorders (ASD) and assess the effects of pathogens on the onset of ASD-like symptoms.

Rational Design and Identification of Harmine-Inspired, N-Heterocyclic DYRK1A Inhibitors Employing a Functional Genomic In Vivo Drosophila Model System.

Deregulation of dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) plays a significant role in developmental brain defects, early-onset neurodegeneration, neuronal cell loss, dementia, and several types of cancer. Herein, we report the discovery of three new classes of N-heterocyclic DYRK1A inhibitors based on the potent, yet toxic kinase inhibitors, harmine and harmol. An initial in vitro evaluation of the small molecule library assembled revealed that the core heterocyclic motifs benzofuranones, oxindoles, and pyrrolones, showed statistically significant DYRK1A inhibition. Further, the utilization of a low cost, high-throughput functional genomic in vivo model system to identify small molecule inhibitors that normalize DYRK1A overexpression phenotypes is described. This in vivo assay substantiated the in vitro results, and the resulting correspondence validates generated classes as architectural motifs that serve as potential DYRK1A inhibitors. Further expansion and analysis of these core compound structures will allow discovery of safe, more effective chemical inhibitors of DYRK1A to ameliorate phenotypes caused by DYRK1A overexpression.

The WNT1G177C mutation specifically affects skeletal integrity in a mouse model of osteogenesis imperfecta type XV

The recent identification of homozygous WNT1 mutations in individuals with osteogenesis imperfecta type XV (OI-XV) has suggested that WNT1 is a key ligand promoting the differentiation and function of bone-forming osteoblasts. Although such an influence was supported by subsequent studies, a mouse model of OI-XV remained to be established. Therefore, we introduced a previously identified disease-causing mutation (G177C) into the murine Wnt1 gene. Homozygous Wnt1G177C/G177C mice were viable and did not display defects in brain development, but the majority of 24-week-old Wnt1G177C/G177C mice had skeletal fractures. This increased bone fragility was not fully explained by reduced bone mass but also by impaired bone matrix quality. Importantly, the homozygous presence of the G177C mutation did not interfere with the osteoanabolic influence of either parathyroid hormone injection or activating mutation of LRP5, the latter mimicking the effect of sclerostin neutralization. Finally, transcriptomic analyses revealed that short-term administration of WNT1 to osteogenic cells induced not only the expression of canonical WNT signaling targets but also the expression of genes encoding extracellular matrix modifiers. Taken together, our data demonstrate that regulating bone matrix quality is a primary function of WNT1. They further suggest that individuals with WNT1 mutations should profit from existing osteoanabolic therapies.

Poly (ADP-Ribose) Polymerase 1 Regulates Cajal-Retzius Cell Development and Neural Precursor Cell Adhesion.

Poly (ADP-ribose) polymerase 1 (PARP1) is a ubiquitously expressed enzyme that regulates DNA damage repair, cell death, inflammation, and transcription. PARP1 functions by adding ADP-ribose polymers (PAR) to proteins including itself, using NAD+ as a donor. This post-translational modification known as PARylation results in changes in the activity of PARP1 and its substrate proteins and has been linked to the pathogenesis of various neurological diseases. PARP1 KO mice display schizophrenia-like behaviors, have impaired memory formation, and have defects in neuronal proliferation and survival, while mutations in genes that affect PARylation have been associated with intellectual disability, psychosis, neurodegeneration, and stroke in humans. Yet, the roles of PARP1 in brain development have not been extensively studied. We now find that loss of PARP1 leads to defects in brain development and increased neuronal density at birth. We further demonstrate that PARP1 loss increases the expression levels of genes associated with neuronal migration and adhesion in the E15.5 cerebral cortex, including Reln. This correlates with an increased number of Cajal–Retzius (CR) cells in vivo and in cultures of embryonic neural progenitor cells (NPCs) derived from the PARP1 KO cortex. Furthermore, PARP1 loss leads to increased NPC adhesion to N-cadherin, like that induced by experimental exposure to Reelin. Taken together, these results uncover a novel role for PARP1 in brain development, i.e., regulation of CR cells, neuronal density, and cell adhesion.

Loss function of Bcr mutation causes gastrointestinal dysmotility and brain developmental defects.

The breakpoint cluster region (BCR) is a protein that originally forms a fusion protein with c-Abl tyrosine kinase and induces leukemia. Researchers have shown that BCR is enriched in the central nervous system and may contribute to neurological disorders. We aimed to investigate the physiological function of BCR in neural development in the gastrointestinal (GI) tract and brain. Whole-exome sequencing was used to screen for mutations in the BCR. Bcr knockout mice (Bcr-/- , ΔExon 2-22) were generated using the CRISPR/Cas9system. Transit of carmine red dye and glass bead expulsion assays were used to record total and proximal GI transit and distal colonic transit. In an infant with pediatric intestinal pseudo-obstruction, we found a heterozygous de novo mutation (NM_004327.3:c.3072+1G>A) in BCR. Bcr deficiency mice (Bcr-/- ) exhibited growth retardation and impaired gastrointestinal motility. Bcr-/- mice had a prolonged average total GI transit time with increased distal colonic transit and proximal GI transit in isolation. Morphology analysis indicated that Bcr-/- mice had a less number of neurons in the submucosal plexus and myenteric plexus. Bcr-/- mice exhibited apparent structural defects in the brain, particularly in the cortex. Additionally, Bcr- depletion in the mouse cortex altered the expression of Ras homologous (Rho) family small GTPases. BCR mutations are associated with intestinal obstruction in children. Loss of Bcr can cause intestinal dysmotility and brain developmental defects may via regulation of Rho GTPases.