Stages Of Postnatal Development Research Articles

Nasal obstruction during development leads to defective synapse elimination, hypersynchrony, and impaired cerebellar function

Nasal respiratory disorders are linked to craniofacial anomalies and systemic dysfunctions. However, the implications of nasal respiratory disorders on brain development and their subsequent impact on brain functionalization remain largely unknown. Here, we describe that nasal obstruction from postnatal developmental stages in mice precipitates deficits in cerebellum-associated behaviors and compromised refinement and maturation of neural circuits in the cerebellum. We show that mice with nasal obstruction during developmental phases exhibit marked impairments in motor function and exhibit increased immobility time in forced swimming test. Additionally, we identified critical periods during which nasal respiration is essential for optimizing motor function and preserving mental health. Our study also reveals that nasal obstruction in mice disrupts the typical developmental process of synapse elimination in the cerebellum and hinders the normal transition of activity patterns in cerebellar Purkinje cell populations during development. Through comparing activity patterns in mouse models subjected to nasal obstruction at various stages, we suggest that the maturation of specific activity pattern among Purkinje cell populations is fundamental to the functional integrity of the cerebellum. Our findings highlight the indispensable role of adequate nasal respiration during development for the establishment and functional integrity of neural circuits, thereby significantly affecting brain function.

Element Changes Occurring in Brain Point at the White Matter Abnormalities in Rats Exposed to the Ketogenic Diet During Prenatal Life.

A large number of clinical studies demonstrate that the ketogenic diet (KD) may be an effective approach to the reduction of epileptic seizures in children and adults. Such dietary therapy could also help pregnant women with epilepsy, especially since most antiseizure drugs have teratogenic action. However, there is a lack of medical data, considering the safety of using KD during gestation for the progeny. Therefore, we examined the influence of KD used prenatally in rats on the elemental composition of the selected brain regions in their offspring. For this purpose, synchrotron radiation-induced X-ray fluorescence (SR-XRF) microscopy was utilized, and elements such as P, S, K, Ca, Fe, and Zn were determined. Moreover, to verify whether the possible effects of KD are temporary or long-term, different stages of animal postnatal development were taken into account in our experiment. The obtained results confirmed the great applicability of SR-XRF microscopy to track the element changes occurring in the brain during postnatal development as well as those induced by prenatal exposure to the high-fat diet. The topographic analysis of the brains taken from offspring of mothers fed with KD during pregnancy and appropriate control individuals showed a potential influence of such dietary treatment on the brain levels of elements such as P and S. In the oldest progeny, a significant reduction of the surface of brain areas characterized by an increased P and S content, which histologically/morphologically correspond to white matter structures, was noticed. In turn, quantitative elemental analysis showed significantly decreased levels of Fe in the striatum and white matter of 30-day-old rats exposed prenatally to KD. This effect was temporary and was not noticed in adult animals. The observed abnormalities may be related to the changes in the accumulation of sphingomyelin and sulfatides and may testify about disturbances in the structure and integrity of the myelin, present in the white matter.

Correlations between Metabolic Parameters, Blood Cytokine Levels, and Behavioral Parameters in Male and Female Rats of Different Age after Intrauterine Stress.

We studied interrelationships between behavioral parameters, metabolic processes, and cytokine content in the blood of male and female rats at different stages of postnatal ontogeny after intrauterine stress (mothers were forced to swim in cold water from the 10th to the 16th day of pregnancy). Correlations between behavioral and metabolic parameters in prenatally stressed rats were revealed at an earlier age (day 21 of life) than in controls. In comparison with intact rats, in males exposed to intrauterine stress no relationships between these parameters were revealed at older age, while in females, their direction and character change on day 60 of life. In prenatally stressed males, correlations of the blood levels of IL-6 were revealed: inverse relationships with behavioral parameters on the days 21 and 30 and direct relationships with metabolic parameters on day 60 of life. In prenatally stressed females on day 30 of life, we observed negative correlations between IL-4 levels and metabolic parameters that were absent under normal conditions. Thus, intrauterine stress leads to reorganization of the relationships between the parameters of metabolic and immune processes, which are essential for the purposeful behavior of mammals. The effects of stress seem to depend on the sex of the offspring and stage of postnatal development.

Nitric oxide synthase system in the brain development of neonatal hypothyroid rats

Thyroid hormones play an important morphogenetic role during the fetal and neonatal periods and regulate numerous metabolic processes. In the central nervous system, they control myelination and overall brain development, regional gene expression, and regulation of oxygen consumption. Their deficiency in the fetal and neonatal periods causes severe mental retardation, due to lack of thyroid function, or to iodine deficiency. At the same time, nitric oxide is an atypical neurotransmitter that also has special relevance in neuronal development and plasticity and functions as a vasodilator, regulating cerebral blood flow. Although under physiological conditions it functions as a neuroprotector, in excess it can be neurotoxic. We have studied, by immunocytochemical and Western blot techniques, the evolution of the expression of neuronal and inducible isoforms of the enzyme nitric oxide synthase, and of nitrotyrosine as a marker of protein nitration produced by the presence of nitric oxide, during the early stages of postnatal brain development. We induced hypothyroidism by administering mercaptomethylimidazole to pregnant mothers, from the seventh day of gestation until the sacrifice of the offspring. The results show a delay in the evolution of the expression of the two isoforms of the enzyme nitric oxide synthase in hypothyroid animals, followed by an anomalous overexpression in later stages. Finally, the expression of nitrotyrosine follows an evolution that is synchronized with that shown by both isoenzymes in control and hypothyroid animals.

Cell Type-Specific Profiles and Developmental Trajectories of Transcriptomes in Primate Prefrontal Layer 3 Pyramidal Neurons: Implications for Schizophrenia.

In schizophrenia, impaired working memory is associated with transcriptome alterations in layer 3 pyramidal neurons (L3PNs) in the dorsolateral prefrontal cortex (DLPFC). Distinct subtypes of L3PNs that send axonal projections to the DLPFC in the opposite hemisphere (callosal projection [CP] neurons) or the parietal cortex in the same hemisphere (ipsilateral projection [IP] neurons) play critical roles in working memory. However, how the transcriptomes of these L3PN subtypes might shift during late postnatal development when working memory impairments emerge in individuals later diagnosed with schizophrenia is not known. The aim of this study was to characterize and compare the transcriptome profiles of CP and IP L3PNs across developmental transitions from prepuberty to adulthood in macaque monkeys. The authors used retrograde labeling to identify CP and IP L3PNs in the DLPFC of prepubertal, postpubertal, and adult macaque monkeys, and used laser microdissection to capture these neurons for RNA sequencing. At all three ages, CP and IP L3PNs had distinct transcriptomes, with the number of genes differentially expressed between neuronal subtypes increasing with age. For IP L3PNs, age-related shifts in gene expression were most prominent between prepubertal and postpubertal animals, whereas for CP L3PNs such shifts were most prominent between postpubertal and adult animals. These findings demonstrate the presence of cell type-specific profiles and developmental trajectories of the transcriptomes of PPC-projecting IP and DLPFC-projecting CP L3PNs in monkey DLPFC. The evidence that IP L3PNs reach a mature transcriptome earlier than CP L3PNs suggests that these two subtypes differentially contribute to the maturation of working memory performance across late postnatal development and that they may be differentially vulnerable to the disease process of schizophrenia at specific stages of postnatal development.

Spatiotemporal Mapping of the Oxytocin Receptor at Single-Cell Resolution in the Postnatally Developing Mouse Brain.

The oxytocin receptor (OXTR) has garnered increasing attention for its role in regulating both mature behaviors and brain development. It has been established that OXTR mediates a range of effects that are region-specific or period-specific. However, the current studies of OXTR expression patterns in mice only provide limited help due to limitations in resolution. Therefore, our objective was to generate a comprehensive, high-resolution spatiotemporal expression map of Oxtr mRNA across the entire developing mouse brain. We applied RNAscope in situ hybridization to investigate the spatiotemporal expression pattern of Oxtr in the brains of male mice at six distinct postnatal developmental stages (P7, P14, P21, P28, P42, P56). We provide detailed descriptions of Oxtr expression patterns in key brain regions, including the cortex, basal forebrain, hippocampus, and amygdaloid complex, with a focus on the precise localization of Oxtr+ cells and the variance of expression between different neurons. Furthermore, we identified some neuronal populations with high Oxtr expression levels that have been little studied, including glutamatergic neurons in the ventral dentate gyrus, Vgat+Oxtr+ cells in the basal forebrain, and GABAergic neurons in layers 4/5 of the cortex. Our study provides a novel perspective for understanding the distribution of Oxtr and encourages further investigations into its functions.

Morphological and molecular aspects of lung development.

Healthy breathing relies on normal morphological and functional development of the lung. This includes different prenatal and postnatal developmental stages. Depending on species and postnatal behavior as nest escapers or nest squatters, the duration of individual developmental phases and the state of differentiation of the lungs at birth differ. However, the sequence and morphology of the lung developmental stages are similar in all mammals, so knowledge gained from animal models about development-specific genetic control and regulatory mechanisms can be translated in principle to the human lung. Functional lung development comprises the maturation of the surfactant system, which is closely linked to the morphological development of the pulmonary acini. Although a number of reviews are found in the literature, a presentation that integrates the morphological and molecular regulatory mechanisms is missing. Therefore, the aim of this article was to provide an up-to-date comprehensive review of the main morphological steps and regulatory mechanisms of lung development, including clinical aspects related to developmental disorders.

Supporting dataset on the content of Cu, Ni Cd, Pb, Zn, Ag, Mg, Fe, Co and Ca in the carcass, gastrointestinal tract tissues and the whole body of nestlings of a small passerine bird, the Eurasian Reed Warbler Acrocephalus scirpaceus from an intensively fertilized fishpond habitat

The dataset presented in this data paper supports “The prenatal assimilation of minerals and metals in the nestlings of a small passerine bird” (Orłowski et al. 2024). The article presents the raw data on the dead nestlings of a small passerine bird, the Eurasian Reed Warbler Acrocephalus scirpaceus breeding in an extensive reedbed (with dominating plant species, the Common Reed Phragmites australis) located in an intensively fertilized fishpond habitat, the Stawy Milickie [Milicz Ponds] Nature Reserve (SW Poland). The data include the description of the age and the concentrations of Cu, Ni Cd, Pb, Zn, Ag, Mg, Fe, Co and Ca measured in the isolated, emptied gastrointestinal tract, the whole body, and carcass of the each individual nestling of a different age and hence a different stage of post-natal development. The dataset includes also some additional information on the breeding biology of the focal species.

Cranial bone microarchitecture in a mouse model for syndromic craniosynostosis.

Crouzon syndrome is a congenital craniofacial disorder caused by mutations in the Fibroblast Growth Factor Receptor 2 (FGFR2). It is characterized by the premature fusion of cranial sutures, leading to a brachycephalic head shape, and midfacial hypoplasia. The aim of this study was to investigate the effect of the FGFR2 mutation on the microarchitecture of cranial bones at different stages of postnatal skull development, using the FGFR2C342Y mouse model. Apart from craniosynostosis, this model shows cranial bone abnormalities. High-resolution synchrotron microtomography images of the frontal and parietal bone were acquired for both FGFR2C342Y/+ (Crouzon, heterozygous mutant) and FGFR2+/+ (control, wild-type) mice at five ages (postnatal days 1, 3, 7, 14 and 21, n = 6 each). Morphometric measurements were determined for cortical bone porosity: osteocyte lacunae and canals. General linear model to assess the effect of age, anatomical location and genotype was carried out for each morphometric measurement. Histological analysis was performed to validate the findings. In both groups (Crouzon and wild-type), statistical difference in bone volume fraction, average canal volume, lacunar number density, lacunar volume density and canal volume density was found at most age points, with the frontal bone generally showing higher porosity and fewer lacunae. Frontal bone showed differences between the Crouzon and wild-type groups in terms of lacunar morphometry (average lacunar volume, lacunar number density and lacunar volume density) with larger, less dense lacunae around the postnatal age of P7-P14. Histological analysis of bone showed marked differences in frontal bone only. These findings provide a better understanding of the pathogenesis of Crouzon syndrome and will contribute to computational models that predict postoperative changes with the aim to improve surgical outcome.

From circuits to lifespan: translating mouse and human timelines with neuroimaging based tractography.

Age is a major predictor of developmental processes and disease risk, but humans and model systems (e.g., mice) differ substantially in the pace of development and aging. The timeline of human developmental circuits is well known. It is unclear how such timelines compare to those in mice. We lack age alignments across the lifespan of mice and humans. Here, we build upon our Translating Time resource, which is a tool that equates corresponding ages during development. We collected 477 time points (n=1,132 observations) from age-related changes in body, bone, dental, and brain processes to equate corresponding ages across humans and mice. We acquired high-resolution diffusion MR scans of mouse brains (n=12) at sequential stages of postnatal development (postnatal day 3, 4, 12, 21, 60) to trace the timeline of brain circuit maturation (e.g., olfactory association pathway, corpus callosum). We found heterogeneity in white matter pathway growth. The corpus callosum largely ceases to grow days after birth while the olfactory association pathway grows through P60. We found that a P3 mouse equates to a human at roughly GW24, and a P60 mouse equates to a human in teenage years. Therefore, white matter pathway maturation is extended in mice as it is in humans, but there are species-specific adaptations. For example, olfactory-related wiring is protracted in mice, which is linked to their reliance on olfaction. Our findings underscore the importance of translational tools to map common and species-specific biological processes from model systems to humans.

Influence of subchronic exposure to manganese carried by female rats during pregnancy on the behavioral and cognitive abilities of their offspring at later stages of postnatal development

The study evaluated the effects of prenatal exposure to manganese (Mn) on the functional state of offspring at later stages of postnatal development (PND). Female rats were treated with MnSO4·5H2O in the diet at a dose of 1433 mg/kg starting 28 days prior to breeding and through gestation. The pregnancy proceeded normally, no physical abnormalities were observed. There was a lag in physical development of the offspring, which was characterized by a later opening of the eyes, the formation of a coat and the eruption of incisors, the weight gain was attenuated from PND 0-84. Offspring had hyperactive behavior and deterioration in spatial learning and memory. The level of Mn in the blood serum and cerebral cortex was higher than the control values by 11 % and 53 % respectively. The acetylcholinesterase level in the serum was higher by 47 %. These findings highlight the risk of prenatal exposure to subchronic doses of Mn.

Single-Nucleus RNA-Seq Reveals Spermatogonial Stem Cell Developmental Pattern in Shaziling Pigs.

Normal testicular development ensures the process of spermatogenesis, which is a complex biological process. The sustained high productivity of spermatogenesis throughout life is predominantly attributable to the constant proliferation and differentiation of spermatogonial stem cells (SSCs). The self-renewal and differentiation processes of SSCs are strictly regulated by the SSC niche. Therefore, understanding the developmental pattern of SSCs is crucial for spermatogenesis. The Shaziling pig is a medium-sized indigenous pig breed originating from central China. It is renowned for its superior meat quality and early male sexual maturity. The spermatogenic ability of the boars is of great economic importance to the pig industry. To investigate testicular development, particularly the pattern of SSC development in Shaziling pigs, we used single-cell transcriptomics to identify gene expression patterns in 82,027 individual cells from nine Shaziling pig testes at three key postnatal developmental stages. We generated an unbiased cell developmental atlas of Shaziling pig testicular tissues. We elucidated the complex processes involved in the development of SSCs within their niche in the Shaziling pig. Specifically, we identified potential marker genes and cellular signaling pathways that regulate SSC self-renewal and maintenance. Additionally, we proposed potential novel marker genes for SSCs that could be used for SSC isolation and sorting in Shaziling pigs. Furthermore, by immunofluorescence staining of testicular tissues of different developmental ages using marker proteins (UCHL1 and KIT), the developmental pattern of the spermatogonia of Shaziling pigs was intensively studied. Our research enhances the comprehension of the development of SSCs and provides a valuable reference for breeding Shaziling pigs.

Reelin Regulates Developmental Desynchronization Transition of Neocortical Network Activity.

During the first and second stages of postnatal development, neocortical neurons exhibit a wide range of spontaneous synchronous activity (SSA). Towards the end of the second postnatal week, the SSA is replaced by a more sparse and desynchronized firing pattern. The developmental desynchronization of neocortical spontaneous neuronal activity is thought to be intrinsically generated, since sensory deprivation from the periphery does not affect the time course of this transition. The extracellular protein reelin controls various aspects of neuronal development through multimodular signaling. However, so far it is unclear whether reelin contributes to the developmental desynchronization transition of neocortical neurons. The present study aims to investigate the role of reelin in postnatal cortical developmental desynchronization using a conditional reelin knockout (RelncKO) mouse model. Conditional reelin deficiency was induced during early postnatal development, and Ca2+ recordings were conducted from organotypic cultures (OTCs) of the somatosensory cortex. Our results show that both wild type (wt) and RelncKO exhibited an SSA pattern during the early postnatal week. However, at the end of the second postnatal week, wt OTCs underwent a transition to a desynchronized network activity pattern, while RelncKO activity remained synchronous. This changing activity pattern suggests that reelin is involved in regulating the developmental desynchronization of cortical neuronal network activity. Moreover, the developmental desynchronization impairment observed in RelncKO was rescued when RelncKO OTCs were co-cultured with wt OTCs. Finally, we show that the developmental transition to a desynchronized state at the end of the second postnatal week is not dependent on glutamatergic signaling. Instead, the transition is dependent on GABAAR and GABABR signaling. The results suggest that reelin controls developmental desynchronization through GABAAR and GABABR signaling.

Sympathetic nerve signals: orchestrators of mammary development and stem cell vitality.

The mammary gland is a dynamic organ that undergoes significant changes at multiple stages of postnatal development. Although the roles of systemic hormones and microenvironmental cues in mammary homeostasis have been extensively studied, the influence of neural signals, particularly those from the sympathetic nervous system, remains poorly understood. Here, using a mouse mammary gland model, we delved into the regulatory role of sympathetic nervous signaling in the context of mammary stem cells and mammary development. Our findings revealed that depletion of sympathetic nerve signals results in defective mammary development during puberty, adulthood, and pregnancy, accompanied by a reduction in mammary stem cell number. Through in vitro three-dimensional culture and in vivo transplantation analyses, we demonstrated that the absence of sympathetic nerve signals hinders mammary stem cell self-renewal and regeneration, while activation of sympathetic nervous signaling promotes these capacities. Mechanistically, sympathetic nerve signals orchestrate mammary stem cell activity and mammary development through the ERK signaling pathway. Collectively, our study unveils the crucial roles of sympathetic nerve signals in sustaining mammary development and regulating mammary stem cell activity, offering a novel perspective on the involvement of the nervous system in modulating adult stem cell function and organ development.

Sensory Stimulation-dependent Npas4 Expression in the Olfactory Bulb during Early Postnatal Development.

The development of the olfactory system is influenced by sensory inputs, and it maintains neuronal generation and plasticity throughout the lifespan. The olfactory bulb contains a higher proportion of interneurons than other brain regions, particularly during the early postnatal period of neurogenesis. Although the relationship between sensory stimulation and olfactory bulb development during the postnatal period has been well studied, the molecular mechanisms have yet to be identified. In this study, we used western blotting and immunohistochemistry to analyze the expression of the transcription factor Npas4, a neuron-specific immediate-early gene that acts as a developmental regulator in many brain regions. We found that Npas4 is highly expressed in olfactory bulb interneurons during the early postnatal stages and gradually decreases toward the late postnatal stages. Npas4 expression was observed in all olfactory bulb layers, including the rostral migratory stream, where newborn neurons are generated and migrate to the olfactory bulb. Under sensory deprivation, the olfactory bulb size and the number of olfactory bulb interneurons were reduced. Furthermore, Npas4 expression and the expression of putative Npas4 downstream molecules were decreased. Collectively, these findings indicate that Npas4 expression induced by sensory input plays a role in the formation of neural circuits with excitatory mitral/tufted cells by regulating the survival of olfactory bulb interneurons during the early stages of postnatal development.

Prenatal and postnatal neuroimmune interactions in neurodevelopmental disorders.

The intricate relationship between immune dysregulation and neurodevelopmental disorders (NDDs) has been observed across the stages of both prenatal and postnatal development. In this Review, we provide a comprehensive overview of various maternal immune conditions, ranging from infections to chronic inflammatory conditions, that impact the neurodevelopment of the fetus during pregnancy. Furthermore, we examine the presence of immunological phenotypes, such as immune-related markers and coexisting immunological disorders, in individuals with NDDs. By delving into these findings, we shed light on the potential underlying mechanisms responsible for the high occurrence of immune dysregulation alongside NDDs. We also discuss current mouse models of NDDs and their contributions to our understanding of the immune mechanisms underlying these diseases. Additionally, we discuss how neuroimmune interactions contribute to shaping the manifestation of neurological phenotypes in individuals with NDDs while also exploring potential avenues for mitigating these effects.

Adenosine and Cortical Plasticity.

Brain plasticity is the ability of the nervous system to change its structure and functioning in response to experiences. These changes occur mainly at synaptic connections, and this plasticity is named synaptic plasticity. During postnatal development, environmental influences trigger changes in synaptic plasticity that will play a crucial role in the formation and refinement of brain circuits and their functions in adulthood. One of the greatest challenges of present neuroscience is to try to explain how synaptic connections change and cortical maps are formed and modified to generate the most suitable adaptive behavior after different external stimuli. Adenosine is emerging as a key player in these plastic changes at different brain areas. Here, we review the current knowledge of the mechanisms responsible for the induction and duration of synaptic plasticity at different postnatal brain development stages in which adenosine, probably released by astrocytes, directly participates in the induction of long-term synaptic plasticity and in the control of the duration of plasticity windows at different cortical synapses. In addition, we comment on the role of the different adenosine receptors in brain diseases and on the potential therapeutic effects of acting via adenosine receptors.

The expression of the surfactant proteins SP-A and SP-B during postnatal alveolarization of the rat lung.

Surfactant-specific proteins (SP) are responsible for the functional and structural integrity as well as for the stabilization of the intra-alveolar surfactant. Morphological lung maturation starts in rat lungs after birth. The aim of this study was to investigate whether the expression of the hydrophilic SP-A and the hydrophobic SP-B is associated with characteristic postnatal changes characterizing morphological lung maturation. Stereological methods were performed on the light microscope. Using immunohistochemical and molecular biological methods (Western Blot, RT-qPCR), the SP-A and SP-B of adult rat lungs and of those with different postnatal developmental stages (3, 7, 14 and 21 days after birth) were characterized. As signs of alveolarization the total septal surface and volume increased and the septal thickness decreased. The significantly highest relative surface fraction of SP-A labeled alveolar epithelial cells type II (AEII) was found together with the highest relative SP-A gene expression before the alveolarization (3th postnatal day). With the downregulation of SP-A gene expression during and after alveolarization (between postnatal days 7 and 14), the surface fraction of the SP-A labeled AEII also decreased, so they are lowest in adult animals. The surface fraction of SP-B labeled AEII and the SP-B gene expression showed the significantly highest levels in adults, the protein expression increased also significantly at the end of morphological lung maturation. There were no alterations in the SP-B expression before and during alveolarization until postnatal day 14. The protein expression as well as the gene expression of SP-A and SP-B correlated very well with the total surface of alveolar septa independent of the postnatal age. The expression of SP-A and SP-B is differentially associated with morphological lung maturation and correlates with increased septation of alveoli as indirect clue for alveolarization.

Developmental patterns of extracellular matrix molecules in the embryonic and postnatal mouse hindbrain.

Normal brain development requires continuous communication between developing neurons and their environment filled by a complex network referred to as extracellular matrix (ECM). The ECM is divided into distinct families of molecules including hyaluronic acid, proteoglycans, glycoproteins such as tenascins, and link proteins. In this study, we characterize the temporal and spatial distribution of the extracellular matrix molecules in the embryonic and postnatal mouse hindbrain by using antibodies and lectin histochemistry. In the embryo, hyaluronan and neurocan were found in high amounts until the time of birth whereas versican and tenascin-R were detected in lower intensities during the whole embryonic period. After birth, both hyaluronic acid and neurocan still produced intense staining in almost all areas of the hindbrain, while tenascin-R labeling showed a continuous increase during postnatal development. The reaction with WFA and aggrecan was revealed first 4th postnatal day (P4) with low staining intensities, while HAPLN was detected two weeks after birth (P14). The perineuronal net appeared first around the facial and vestibular neurons at P4 with hyaluronic acid cytochemistry. One week after birth aggrecan, neurocan, tenascin-R, and WFA were also accumulated around the neurons located in several hindbrain nuclei, but HAPLN1 was detected on the second postnatal week. Our results provide further evidence that many extracellular macromolecules that will be incorporated into the perineuronal net are already expressed at embryonic and early postnatal stages of development to control differentiation, migration, and synaptogenesis of neurons. In late postnatal period, the experience-driven neuronal activity induces formation of perineuronal net to stabilize synaptic connections.

Impaired T3 uptake and action in MCT8-deficient cerebral organoids underlie Allan-Herndon-Dudley syndrome.

Patients with mutations in the thyroid hormone (TH) cell transporter monocarboxylate transporter 8 (MCT8) gene develop severe neuropsychomotor retardation known as Allan-Herndon-Dudley syndrome (AHDS). It is assumed that this is caused by a reduction in TH signaling in the developing brain during both intrauterine and postnatal developmental stages, and treatment remains understandably challenging. Given species differences in brain TH transporters and the limitations of studies in mice, we generated cerebral organoids (COs) using human induced pluripotent stem cells (iPSCs) from MCT8-deficient patients. MCT8-deficient COs exhibited (i) altered early neurodevelopment, resulting in smaller neural rosettes with thinner cortical units, (ii) impaired triiodothyronine (T3) transport in developing neural cells, as assessed through deiodinase-3-mediated T3 catabolism, (iii) reduced expression of genes involved in cerebral cortex development, and (iv) reduced T3 inducibility of TH-regulated genes. In contrast, the TH analogs 3,5-diiodothyropropionic acid and 3,3',5-triiodothyroacetic acid triggered normal responses (induction/repression of T3-responsive genes) in MCT8-deficient COs, constituting proof of concept that lack of T3 transport underlies the pathophysiology of AHDS and demonstrating the clinical potential for TH analogs to be used in treating patients with AHDS. MCT8-deficient COs represent a species-specific relevant preclinical model that can be utilized to screen drugs with potential benefits as personalized therapeutics for patients with AHDS.