The adult cerebellum is involved in modulating most, if not all, behaviors via its direct or indirect projections throughout the central nervous system. Its involvement in higher order behaviors is most prominent in human, where the lateral cerebellum (hemispheres) has expanded along with areas in the cerebral cortex that regulate language, emotions and cognition. An important aspect of wiring of the brain, is how the circuitry is established during normal development and activity, compared to how it is established when a developmental defect occurs, such as an injury that kills cells or a genetic mutation that alters the activity of specific neurons or changes the transcriptional output. One way to assess the impact of these two modes of circuit formation is to compare the robustness of specific behaviors in rodents in the two conditions, and thereby infer what behaviors are normally controlled by specific cerebellar cells/regions and which behavior modules or neural circuits they participate in. Inhibition of groups of neurons in the adult brain has been used to define what behaviors the cells control. While such an approach can define neural circuit function under normal developmental conditions, it does not reveal the underlying ability of the neural circuits to rewire, or wire in a different way when faced with a developmental perturbation. In the latter, cells that normally would be involved in a behavior might no longer control the behavior and instead a new set of neurons might control the behavior. In this chapter, we address these issues by describing what is considered the normal functions of subgroups of the cerebellar nuclei output neurons based on inhibiting/lesioning neurons in the adult and compare this to how the circuits appear to function following disruption of neurons by inhibiting their activity, removing them or introducing gene mutations during development.
Spermatogenesis is composed of three consecutive stages, mitosis, meiosis and spermiogenesis, during which spermatogenic cells undergo continuous molecular and cellular transformation. Regulation of gene expression has been underlying major molecular mechanisms that govern the progressive cell fate determination during spermatogenesis. Besides epigenetic and transcriptional controls, the un-coupled transcription and translation is a common phenomenon conserved across phyla during spermatogenesis. Translational regulation determines the dynamic proteomic landscapes in spermatogenic cells. Aberrant protein synthesis caused by mutations in RNA binding proteins (RBPs) and translation regulators often cast detrimental effects on spermatogenesis in a stage-specific manner, leading to male infertility. Regulation of gene expression at the post-transcriptional and translational levels bear advantages of fast and flexible responses to changing environment, coordination of cellular states including energy and nutrient availability, preservation of genomic fidelity and quantitative and qualitative control of proteins, the functional units of the cell. How cell type-specific translation is regulated during spermatogenesis is largely unclear. In this review, we will first introduce general features of protein synthesis and what have been revealed during mouse spermatogenesis when aberrant protein synthesis occurred. We will then analyze the differential signaling pathways and intracellular factors that cooperatively regulate proteomic landscapes in spermatogenic cells at various stages of spermatogenesis. Protein synthesis is a fundamental mechanism underlying cell fate determination. Taking advantage of current advancements in methodology, future research in this area will unveil the design principles that govern how cells program and maintain functional proteome during development and disease.
This chapter reviews the role of Astrotactin 2 (ASTN2) in cerebellar development and its implications for neurodevelopmental disorders, particularly autism spectrum disorder (ASD). ASTN2 is identified as a critical gene influencing the function of the cerebellum, a brain region traditionally associated with motor control but now recognized for its roles in social cognition and emotional processing. ASTN2 mutations, including deletions and copy number variations, have been linked to increased risks of ASD and other psychiatric conditions. Studies highlight ASTN2's involvement in neuronal migration, synaptic modulation, protein trafficking, and behavior, as evidenced by mouse models displaying ASD-like behaviors when ASTN2 expression is perturbed. Additionally, ASTN2 affects the structure and function of the sole output neuron of the cerebellum, the Purkinje cell, including changes in spine density and synaptic transmission. To bridge the knowledge gap regarding the role of ASTN2 in human neurodevelopmental disorders, human induced pluripotent stem cells are being employed to further investigate ASTN2's function in human neuronal development and physiology. These studies position ASTN2 as a potential target for future therapeutic interventions in ASD and other neurodevelopmental disorders.
Spermatogenesis is a highly coordinated male developmental process essential for passing on genetic information and fertility. The process features a series of complex cellular and genomic transitions. The main objective of this review is to provide a synthesis of changes single-cell genomics have brought to the male germline. This review begins with an account of the journey from rudimentary, low resolution, and throughput microarray technologies to the advanced and sophisticated, high throughput single-cell RNA sequencing (scRNA-seq) technologies that have provided the means for the generation of extensive and comprehensive "cell atlases" of the testis. The review focuses on the resolution of long-standing controversies associated with the spermatogonial stem cells (SSCs) niche regarding continuum of germ cell differentiation, and germ cell differentiation and stem cell specification. The frontiers of single-cell based DNA techniques such as Single-Cell Assay for Transposase-Accessible Chromatin using sequencing (scATAC-seq) and single-cell DNA methylation will then be discussed. We focus on the perinatal period crucial for the epigenetic priming of the foundational stem cell pool and chromatin remodeling that facilitates the histone-to-protamine transition. The regenerative capacity of the germline and the single-cell identified subsets and metabolic gates that are capable of restoring the ability to conceive post-injury tissues are also explored. Finally, we will go over the prospective views on the use of multi-omics and new spatial transcriptomics. These tools not only provide molecular components of interest within the cells, but also the cellular constituents of the seminiferous tubule and their spatial location within the tubule. This novel information will help translate the molecular discovery into potential clinical applications for male infertility treatment.
Adult Leydig cells (ALCs) are specialized androgen-producing cells that originate from stem Leydig cells (SLCs) during pubertal development. SLCs reside in the testicular interstitial compartment, either centrally or near peritubular myoid cells and vasculature. While their precise origin remains under investigation, prevailing evidence suggests SLCs derive from mesonephros-derived mesenchymal cells, though contributions from neural crest or coelomic epithelium lineages have been proposed. Luteinizing hormone (LH) is a critical regulator of Leydig cell maturation and steroidogenic function, yet the mechanisms enabling SLCs to acquire responsiveness to LH/growth factor signals remain incompletely characterized. Current models suggest paracrine factors from Sertoli cells, peritubular myoid cells, immune cells, or germ cells may orchestrate the early SLC-to-Leydig cell transition prior to LH sensitivity. Fetal Leydig cell-derived androgens may also prime ALC development. Postnatally, LH signaling drives both proliferative expansion (yielding ∼25 million Leydig cells in adult rats) and terminal differentiation of intermediate progenitor stages, ultimately establishing the testosterone-secreting ALC population essential for male reproductive function.
The germline cyst is a highly conserved structure that supports the proliferation and differentiation of gametes across many species. Germline cysts form when germ cells divide with incomplete cytokinesis, resulting in stable intercellular bridges that act as cytoplasmic channels between sister cells. In mammals, both male and female germ cells develop and enter meiosis within cysts, and disruption of intercellular bridges leads to defects in meiotic progression and gamete formation. However, we are only beginning to understand the biological mechanisms uniquely needed in the germline that are enabled by this structure. In this review, we provide an overview of germ cell development in cysts, from cyst formation through gamete individualization, culminating in the production of mature spermatozoa and oocytes. We highlight studies that examine the functional roles of intercellular bridges and discuss the potential advantages of gamete development within a syncytium, including intercellular communication, resource sharing, and coordinated cell fate decisions. Understanding the formation and breakdown of the cyst as well as the functions it supports will be essential for advancing our understanding of mammalian gametogenesis and for leveraging this knowledge to improve in vitro approaches for gamete generation.
Late-onset neurodegenerative diseases have long been conceptualized as disorders arising from cumulative cellular stress and age-related decline, with pathology emerging at the time of symptom onset. However, emerging evidence challenges this view, suggesting that developmental perturbations may establish early vulnerabilities that predispose specific neuronal populations to degeneration later in life. In the cerebellum, mutations causing spinocerebellar ataxias (SCAs) such as SCA1 and SCA6 affect genes involved in normal circuit formation, resulting in subtle early abnormalities in Purkinje cell activity and connectivity. These alterations seem to be initially buffered by compensatory mechanisms, and the eventual breakdown of homeostatic resilience during midlife may thus be the trigger for disease onset and progression. This developmental perspective reframes late-onset neurodegeneration as a lifelong process shaped by the interplay between early developmental wiring, adaptive compensation, and age-dependent vulnerability. Understanding these early developmental alterations provides critical insight into disease mechanisms and opens new avenues for pre-symptomatic intervention and prevention.
The cerebellum is a hindbrain structure that houses the majority of neurons in the mammalian brain and is involved in motor coordination, balance and higher cognitive processes. Compared to the rest of the brain, cerebellar development is protracted, with neurogenesis continuing postnatally. While the local circuitry of the cerebellum is relatively simple, having the correct proportions of its various cell types is essential for cerebellar function. Remarkably, the neonatal mouse cerebellum is highly regenerative upon injury at birth, utilizing context- and age-dependent regenerative strategies to ensure robust and efficient repair. Here, we provide an overview of how different lineages within the cerebellum interact during development and discuss the mechanisms of scaling, where the earlier-born neurons regulate the survival and proportional expansion of other cell types. We give examples of disorders where the scaling could be disrupted, perinatal injuries that affect the cerebellum and potential regenerative mechanisms in the brain. Furthermore, we discuss how the neonatal cerebellum regenerates the correct cell types in the appropriate proportions. Finally, we summarize the cell-intrinsic and -extrinsic mechanisms that regulate progenitor behaviors during postnatal cerebellar development and regeneration, specifically focusing on the nestin-expressing progenitors of the postnatal cerebellum.
The gross structure of the human cerebellum is divided into an intricate pattern of lobules by fissures that extend across the surface. The folded shape, and its emergence during development, presents an exciting problem of tissue morphogenesis. While other structures in the human brain are folded, the cerebellum is a tractable model for studying neural tissue folding. The cerebellum folds in small, inexpensive model systems including the mouse where there is a wealth of descriptive and mutational data. Computational models have also been developed to predict how cerebellar folding may be regulated, generating testable hypotheses. The relatively simple folding pattern of the murine cerebellum, and the well-established genetic tools provide an exciting opportunity to challenge hypotheses and to dissect the underlying regulation that controls the amount and pattern of folding. In this chapter a descriptive analysis of the folding of the murine cerebellum is given. A modeling framework for understanding the mechanics of folding, explicit to the cerebellum, is discussed in terms of the developmental data. Then several categories of folding phenotypes, from various perturbations, are discussed in terms of the modeling and the cell and tissue-level mechanics predicted to be involved. Finally, the chapter concludes with brief comments about the future directions of the field.
Cell migration is a fundamental process essential for homeostasis, disease progression, and developmental biology. This review explores the mechanisms of cell migration, focusing on both single-cell and collective migration modes, and highlights their roles in early development. We examine the characteristics of amoeboid and mesenchymal migration, emphasizing their regulation and implications across various classical developmental models. By analyzing examples of single-cell migration, such as primordial germ cell migration in zebrafish and Drosophila melanogaster, and examples of collective cell migration in the lateral line of zebrafish, border cells, and testis myotubes in Drosophila, we illustrate the complexity and significance of cell-cell interactions, cell-matrix interactions, and the chemical and mechanical cues that drive migration. The review also highlights the "supracellular organization" observed in many systems where supracellular actomyosin cables are present, which allow for coordinated and cooperative movement. This cooperativity is crucial for effective positioning and function, ensuring proper tissue formation and responsive adaptation to environmental cues. This review provides insights and raises questions about the mechanisms of cell migration during development, supporting the idea that cells never migrate entirely alone. We propose that even in those cases normally described as single cell migration, some degree of collectiveness or cooperation is involved, suggesting that during development, cells always migrate in collective coordination when forming complex tissue and organ structures.
Meiosis exclusively occurs in the germ cells of eukaryotic organisms during sexual reproduction. A striking feature of this process is meiotic recombination, which results in the formation of DNA crossovers between the paternal and maternal chromosomes. Crossovers are pivotal in ensuring the accurate segregation of chromosomes during gamete formation, resulting in offspring that possess half of their progenitor's chromosome complement. Furthermore, crossovers play a crucial role in promoting genetic diversity within the offspring. The process of meiotic recombination is implemented in meiotic chromosomes by direct interaction between recombination complexes and the underlying loop/axis architecture of chromosomes. Consequently, CO patterning is subject to tight regulation by meiotic chromosome structures. Significant advances have been made in recent years in understanding the molecular mechanisms underlying these processes. We summarize the prevailing perspective on the organization of meiotic chromosomes, the meiotic recombination, with particular emphasis on CO patterning, and their interaction. We also provide a review of the current models for potential mechanisms for these processes.
The increasing incidence of kidney diseases has highlighted the need for in vitro experimental models to mimic disease development and to test new therapeutic approaches. Traditional two-dimensional in vitro experimental models are not fully able to recapitulate renal diseases. Instead, kidney organoids represent three-dimensional models that better mimic the human organ from both structural and functional points of view. Human pluripotent stem cells (PSCs), both embryonic and induced, are ideal sources for generating renal organoids. These organoids contain all renal cell types and the protocols to differentiate PSCs into renal organoids consist of three different stages that recapitulate embryonic development: mesodermal induction, nephron progenitor formation, and nephron differentiation. Recently it has been establish a renal organoid model where collecting ducts are also present. In this case, the presence of ureteric bud progenitor cells is essential. Renal organoids are particularly useful for studying genetic diseases, by introducing the specific mutations in PSCs by genome editing or generating organoids from patient-derived PSCs. Moreover, renal organoids represent promising models in toxicology studies and testing new therapeutic approaches. Renal organoids can be established also from adult stem cells. This type of organoid, named tubuloid, is composed only of epithelial cells and recapitulates the tissue repair process. The tubuloids can be generated from adult stem or progenitor cells, obtained from renal biopsies or urine, and are promising in vitro models for studying tubular functions, diseases, and regeneration. Tubuloids can be derived from patients and permit the study of genetic diseases, performing personalized drug screening and modeling renal pathologies.
In mammalian testes, GFRα1-positive spermatogonia, including spermatogonial stem cells (SSCs), are maintained in the basal compartment of seminiferous tubules. These cells actively migrate along the tubules within an 'open' niche, under the regulation of temporally fluctuating GDNF and retinoic acid (RA) signals, as well as constitutive FGF. In contrast, a newly discovered SSC niche exists in the Sertoli valve (SV) region at the terminal end of the seminiferous tubules, influenced by adjacent SOX17-positive rete testis. The SV epithelium, composed of specialized Sertoli cells, constitutively expresses GDNF and CYP26A1, an RA-degrading enzyme, supporting stable maintenance of GFRα1-positive spermatogonia in a region-specific manner. Unlike those in convoluted seminiferous tubules, SV Sertoli cells in rats and hamsters retain proliferative capacity in adulthood. In hamsters, these Sertoli cells relocate distally to support spermatogenesis, suggesting the presence of Sertoli cell progenitors in the SV region. This review discusses SV formation and its role as a 'closed' niche in mammalian spermatogenesis.
The accurate representation of sound in the central auditory pathway of mammals depends on the cochlea, the peripheral sensory organ, which is optimised to detect acoustic signals with unparalleled temporal precision. Beyond its role in converting acoustic stimuli into electrical signals, the cochlea also plays a key role in shaping the maturation of the auditory pathway during pre-hearing stages. This process is essential for creating the tonotopic maps used to identify a broad range of sound frequencies. To achieve this extraordinary task, the sensory hair cells and supporting cells of the pre-hearing cochlear sensory epithelium generate spontaneous, sensory-independent Ca2+ signals that propagate along the ascending auditory pathway. Here we review the current understanding of how the different Ca2+ signals are generated within the developing cochlea, how they interact to regulate the activation of the auditory afferent fibres, and how they ultimately contribute to the establishment of a mature auditory system pathway. Remarkably, a partial regression to an immature developmental stage occurs in the ageing cochlea, correlated with age-related hearing loss. Increasing our understanding of how the cochlear epithelium changes during all stage of life will inform future therapies for preventing and to reverse hearing loss.
The aberrant regulation of renal progenitor cells during kidney development leads to congenital kidney anomalies and dysplasia. Recently, significant progress has been made in understanding the metabolic needs of renal progenitor cells during mammalian kidney development, with evidence indicating that multiple metabolic pathways play essential roles in determining the cell fates of distinct renal progenitor populations. This review summarizes recent findings and explores the prospects of integrating this novel information into current diagnostic and treatment strategies for renal diseases. Reciprocal interactions between various embryonic kidney progenitor populations establish the foundation for normal kidney organogenesis, with the three principal kidney structures-the nephrons, the collecting duct network, and the stroma-being generated by nephron progenitor cells, ureteric bud/collecting duct progenitor cells, and interstitial progenitor cells. While energy metabolism is well recognized for its importance in organism development, physiological function regulation, and responses to environmental stimuli, research has primarily focused on nephron progenitor metabolism, highlighting its role in maintaining self-renewal. In contrast, studies on the metabolic requirements of ureteric bud/collecting duct and stromal progenitors remain limited. Given the importance of interactions between progenitor populations during kidney development, further research into the metabolic regulation of self-renewal and differentiation in ureteric bud and stromal progenitor cells will be critical.
"No cell is an island" - highlights the interconnectedness of cellular behavior and the extracellular matrix (ECM). Cell migration is inherently contextual, as cells navigate and adapt to their environments, reshaping the ECM while being influenced by its properties. This review focuses on the mechanical characteristics of the ECM-specifically its architecture, porosity, dynamics, and stiffness-and how these attributes affect cell behavior and migration strategies. We discuss how the mechanical properties are modulated by the composition and arrangement of ECM components and the role of enzymatic activities, including crosslinking and matrix metalloproteinases. By presenting examples from vertebrate and invertebrate developmental models, we demonstrate how ECM mechanics dictate cell migration at various biological scales. Additionally, we examine the importance of cell-matrix adhesions in regulating migration speed and direction. While in vitro studies have advanced our understanding of the molecular mechanisms at play, significant questions persist regarding the regulation of cell migration by ECM mechanics in vivo. Ultimately, this synthesis aims to illuminate the complexities of cell-ECM mechanical interactions, pointing the way for future research that may unveil novel insights into how ECM mechanics influences cell migration during development and disease.
Despite the progress in identifying genetic and molecular contributors to dystonia, the synaptic and circuit mechanisms that disrupt motor maturation and serve as the substrate for disease pathogenesis are only beginning to emerge. In this chapter, we highlight evidence implicating the olivocerebellar node as a key site of pathogenesis in the dystonia network. As an example of aberrant olivocerebellar circuit activity leading to dystonia, here we examine a mouse model in which excitatory neurotransmission is silenced at inferior olive to cerebellum synapses upon Vglut2 mediated conditional complex spike knockout (CSKO mice). In this model, dystonic postures emerge postnatally in a time-locked manner coinciding with disrupted olivocerebellar circuit refinement. These mice fail to undergo typical transitions from rudimentary to coordinated motor behaviors, implicating cerebellar activity as a critical driver of motor maturation, which we link to clinical observations from human patients. Anatomical and physiological evidence suggests that loss of climbing fiber signaling impairs Purkinje cell and cerebellar nuclei development, disrupting cerebellar output. We propose that a subset of dystonia etiologies, conceptually, reflect perpetual immaturity of motor commands due to these cerebellar circuit deficits, potentially identifying critical periods to restore proper motor function. Formulating dystonia as an immature motor state raises the intriguing perspective that broader etiologies of dystonia (both cerebellar and otherwise) may in part reflect a reversion of the developed motor network, similar to how strokes and neurodegenerative diseases "uncover" primitive reflexes. As a result, the CSKO mouse model provides a framework for understanding diverse etiologies of dystonia and highlights cerebellar output as a promising therapeutic target across developmental and acquired forms.
With its limited diversity of neuronal types and stereotyped cellular organisation, the cerebellum is an excellent model for complex brain development. It exemplifies how simple patterning rules can give rise to complex neural circuits. The entirety of populations of excitatory and inhibitory neurons is characterised by the transient expression of either Atonal1 (Atoh1) or Ptf1a, respectively, and derived from a spatially defined population of Sox2-positive precursors. We present a model where the decision to make Atoh1 over Ptf1a lineage neurons is dictated by inductive cell-cell interactions at the posterior boundary with non-neural roof plate cells at the rhombic lip. The type of Atoh1+ve or Ptf1a+ve cell generated is dictated by a shared temporal code invested in the Sox2-expressing progenitor pool in the ventricular zone of dorsal rhombomere 1. An additional long-lived pool of Sox2 progenitors in the prospective white matter gives rise to glial cells (astrocytes) and later born interneurons, the latter of which also transiently express Ptf1a. Temporal patterning of progenitors generates neuronal diversity and offers a potent substrate for adaptation. In particular, fine-grained temporal patterning of progenitors feeding early rhombic lip derivatives dictates the connections of the cerebellum through specifying cerebellar nucleus output neurons which influence the scaling of the cortex of the cerebellum. In the human cerebellum, scaling involves species-specific adaptations that co-evolved within the human cerebral cortex.
To optimize nutrient absorption and protect against physical, chemical, and microbial threats, the small intestine undergoes extensive remodeling during embryogenesis and postnatal development to establish peristalsis, expand absorptive surface area, and modulate epithelial turnover. Each developmental stage demands precise spatiotemporal regulation of cell fate specification and positioning while simultaneously coordinating cell shape changes to drive organogenesis. This chapter examines mammalian small intestinal morphogenesis from late embryogenesis through postnatal maturation, highlighting the interplay between epithelial-mesenchymal signaling, intrinsic actomyosin dynamics, and external mechanical forces in gut tube elongation, smooth muscle patterning, villus morphogenesis, and crypt formation. Once the crypt-villus axis is established, epithelial cells employ dynamic extracellular matrix interactions and cytoskeletal reorganization to migrate toward the villus tip, where they are extruded to maintain high turnover. Insights from animal models and in vitro organoid systems reveal how tissue architecture not only emerges from but reinforces epithelial maturation and functional specialization.
Gustation, or the sense of taste, is essential for distinguishing harmful and nutritious substances, and therefore crucial for health and survival. Taste buds (TBs) located in specialized gustatory papillae on the dorsal surface of the tongue are assemblages of specialized epithelial cells called taste receptor cells (TRCs). With the help of saliva, TRCs transduce sweet, sour, salt, bitter and umami stimuli into electrochemical signals that are transmitted to the brain via gustatory sensory neurons of the VIIth and IXth cranial ganglia. TBs in the anterior tongue are derived from embryonic ectoderm, while those in the posterior tongue arise from the endoderm. However, regardless of origin and location, all cells in adult taste buds are continually and reliably renewed, such that the sense of taste remains constant. Disruption of this regenerative process in disease or injury can lead to taste dysfunction, or dysgeusia, which negatively impacts quality of life. Decades of research into development and maintenance of adult taste epithelium have revealed molecular and cellular mechanisms underlying these processes. Here, we discuss current findings in the context of the original discoveries related to taste development and regeneration, as well as the transition from developmental to homeostatic mechanisms. Additionally, we review what is currently understood of how cancer therapies cause taste dysfunction and how the taste periphery responds to injury and inflammation. Finally, we consider future directions for the taste field and discuss several outstanding questions for further investigation.