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Development of basket cell axons. (A) original drawing by Santiago Ramon y Cajal of a cerebellar basket cell (B) labeled by Golgi staining demonstrating its characteristic axonal arbors (a), the "pinceaux" formations, around the Purkinje cell body and axon. (B) Basket cell axons synapse preferentially on the Purkinje cell axon initial segment (AIS) under the influence of a gradient of Neurofascin 186, stabilized by Ankyrin G. In Ankyrin G knockout mice, the gradient of Neurofascin is abolished and basket cell axons do not synapse preferentially on the AIS. Abbreviations: ML, molecular layer; PCL, Purkinke cell layer; GCL, granule cell layer. A, Cajal drawing. Original conserved at the Instituto Cajal (CSIC), Madrid (Spain). B is adapted from Huang et al., 2007.
Source publication
The mammalian brain is the most complex organ in the body. It controls all aspects of our bodily functions and interprets the world around us through our senses. It defines us as human beings through our memories and our ability to plan for the future. Crucial to all these functions is how the brain is wired in order to perform these tasks. The bas...
Context in source publication
Context 1
... gradient on the Purkinje cell body and enriched at the axon initial segment, where it binds AnkyrinG ( Ango et al. 2004). Basket cell axons fail to target properly to the axon initial segment when the NF186 gradient is abolished, such as in AnkyrinG knockout mice or following expression of a dominant-negative form of neurofascin in Purkinje cells (Fig. 5). Homophilic interactions between the processes of Bergmann glia and stellate cell axons appear to guide these axons to the Purkinje cell dendrites ( Ango et al. 2008). This involves close homolog of L1 (CHL1), because in CHL1 knockout mice, stellate cell axons fail to properly innervate the Purkinje cell dendrites. In the retina, ...
Citations
... Cortical excitatory projection neurons possess long axons and connect to target neurons in other cortical and subcortical regions . Since a single neuron often projects to multiple targets, both extensive and precise axon branching patterns are required to provide distinct inputs to specific brain regions (Chédotal and Richards, 2010;Greig et al, 2013). Given the complexity of axon trajectories, precise regulation of collateral axon branch formation is vital for generation of a functional brain connectome (Armijo-Weingart and Gallo, 2017). ...
Regulation of directed axon guidance and branching during development is essential for the generation of neuronal networks. However, the molecular mechanisms that underlie interstitial (or collateral) axon branching in the mammalian brain remain unre-solved. Here, we investigate interstitial axon branching in vivo using an approach for precise labeling of layer 2/3 callosal projection neurons (CPNs). This method allows for quantitative analysis of axonal morphology at high acuity and also manipulation of gene expression in well-defined temporal windows. We find that the GSK3β serine/threonine kinase promotes interstitial axon branching in layer 2/3 CPNs by releasing MAP1B-mediated inhibition of axon branching. Further, we find that the tubulin tyr-osination cycle is a key downstream component of GSK3β/MAP1B signaling. These data suggest a cell-autonomous molecular regulation of cortical neuron axon morphology, in which GSK3β can release a MAP1B-mediated brake on interstitial axon branching upstream of the posttranslational tubulin code.
... Brain wiring is an essential developmental process in which neurons project axons that connect to their proper target to form functional circuits. Axonal guidance is mediated by a complex orchestration of attractive and repulsive cues that drive the growth cone to its final destination (Lokmane and Garel, 2014;Chédotal and Richards, 2010). The physiological importance of this developmental process is highlighted by several neurological disorders characterized by aberrant neuronal connections (Van Battum et al., 2015). ...
In response to repulsive cues, axonal growth cones can quickly retract. This requires the prompt activity of contractile actomyosin, which is formed by the non-muscle myosin II (NMII) bound to actin filaments. NMII is a molecular motor that provides the necessary mechanical force at the expense of ATP. Here, we report that this process is energetically coupled to glycolysis and is independent of cellular ATP levels. Induction of axonal retraction requires simultaneous generation of ATP by glycolysis, as shown by chemical inhibition and genetic knock-down of GAPDH. Co-immunoprecipitation and proximal-ligation assay showed that actomyosin associates with ATP-generating glycolytic enzymes and that this association is strongly enhanced during retraction. Using microfluidics, we confirmed that the energetic coupling between glycolysis and actomyosin necessary for axonal retraction is localized to the growth cone and near axonal shaft. These results indicate a tight coupling between on-demand energy production by glycolysis and energy consumption by actomyosin contraction suggesting a function of glycolysis in axonal guidance.
... One of the important classes of proteins working along this complex network of signalling is the transcription modulators. Multiple studies have associated them with the governance of synapse development, growth, and maintenance (Chédotal & Richards, 2010;Polleux et al., 2007;Ross et al., 2003). In the present study, we probed into the role of Beadex (Bx), the Drosophila LIM only (LMO) protein, whose mutant, Bx 7 , showcased strikingly reduced larval crawling activity, and flightlessness, reduced walking and jumping abilities in the adult flies. ...
The appropriate growth of the neurons, accurate organization of their synapses, and successful neurotransmission are indispensable for sensorimotor activities. These processes are highly dynamic and tightly regulated. Extensive genetic, molecular, physiological, and behavioural studies have identified many molecular players and investigated their roles in various neuromuscular processes. In this paper, we show that Beadex (Bx), the Drosophila LIM only (LMO) protein, is required for motor activities and neuromuscular growth of Drosophila. Bx7, a null allele, adult flies are flightless, with reduced walking and jumping activities. The larvae of Bx7, and the RNAi-mediated neuronal-specific knockdown of Bx show drastically reduced crawling behaviour, a diminished synaptic span of the neuromuscular junctions and an increased spontaneous neuronal firing with altered motor patterns in the central pattern generators (CPGs). Microarray studies identified multiple targets of Beadex that are involved in different cellular and molecular pathways, including those associated with the cytoskeleton and mitochondria, that could be responsible for the observed neuromuscular defects. With genetic interaction studies, we further show that Highwire (Hiw), a negative regulator of synaptic growth at the NMJs, negatively regulates Bx, as deficiency of the latter was able to rescue the phenotype of the Hiw null mutant, HiwDN. Thus, our data indicates that Beadex functions downstream of Hiw to regulate the larval synaptic growth and physiology.
... The brain is an extremely complex organ with three main compartments: Cerebrum, brainstem, and cerebellum [1,2]. The cerebrum is necessary for controlling motor and sensory pathways, consciousness, behavior, and memory [3], and cerebral disorders are the most common cause of seizures, visual deficits, mental changes, facial paralysis, circling, and head-turning [4]. ...
Background and Aim
Magnetic resonance imaging (MRI) has been widely used as a non-invasive modality to evaluate neurological organ structures. However, brain MRI studies in cats with neurological signs are limited. This study evaluated the association between patient characteristics, neurological signs, and brain lesion locations identified by MRI. Blood profiles of cats with presumptive inflammatory and structural brain lesions were also determined.
Materials and Methods
Medical records of 114 cats that underwent brain MRI were retrospectively reviewed. Cats were categorized into five groups based on the location of their lesion: Cerebrum, brainstem, cerebellum, multifocal, and non-structural. Patient characteristics, neurological signs, and hematological profiles were obtained from their medical records. Disease classification was categorized based on their etiologies. Associations were determined using Fisher’s exact test. Blood parameters were compared using the Kruskal–Wallis test.
Results
A total of 114 cats met the inclusion criteria. Lesions were identified in the cerebrum (21.1%), brainstem (8.8%), cerebellum (6.1%), multifocal (39.5%), and non-structural (24.6%) of the cats. Common neurological signs included seizure activity (56.1%), cerebellar signs (41.2%), and anisocoria (25.4%). The most common brain abnormality was inflammation (40.4%). There was no significant difference in hematological profiles between cats with presumptive inflammatory and non-inflammatory brain lesions. Neutrophils, platelets, total protein, and globulin concentrations were higher in cats with structural brain lesions.
Conclusion
The most common neurological signs and brain disease category were seizure activity and inflammation, respectively. However, the hematological profile did not predict inflammatory and structural brain lesions.
... Mechanically guided cell growth can couple local control mechanisms to global tissue structure and topology [52]. The question if stress (force) or strain (deformation) are the driving mechanism may depend on whether a tissue is predominantly serially or parallelly connected [53]. In the Arabidopsis shoot apical meristem, local topology correlates with turgor pressure rather than cell wall mechanical properties, suggesting an active role of pressure for tissue topology and patterning since cell growth in plants is physically controlled by turgor pressure royalsocietypublishing.org/journal/rsif J. R. Soc. ...
... Mechanisms of protrusion outgrowth are linked to cell migration and involve cell adhesion and actin polymerization [58]. These processes are guided by various environmental cues, including matrix rigidity, anisotropy, growth factors and even electromagnetic fields [52,53,59]. ...
Network analysis is a well-known and powerful tool in molecular biology. More recently, it has been introduced in developmental biology. Tissues can be readily translated into spatial networks such that cells are represented by nodes and intercellular connections by edges. This discretization of cellular organization enables mathematical approaches rooted in network science to be applied towards the understanding of tissue structure and function. Here, we describe how such tissue abstractions can enable the principles that underpin tissue formation and function to be uncovered. We provide an introduction into biologically relevant network measures, then present an overview of different areas of developmental biology where these approaches have been applied. We then summarize the general developmental rules underpinning tissue topology generation. Finally, we discuss how generative models can help to link the developmental rule back to the tissue topologies. Our collection of results points at general mechanisms as to how local developmental rules can give rise to observed topological properties in multicellular systems.
... The growth of one-dimensional structures is a universal phenomenon in physical and living systems, e.g., nanowires [1] and nerves [2,3]. During the development, remodeling, and regeneration of the brain, axons are of importance for shaping the nervous system [3][4][5][6][7]. Active forces generated by the cytoskeleton and extracellular environment play a key role in axonal growth [2,[8][9][10]. ...
Growing axons are one-dimensional active structures that are important for wiring the brain and repairing nerves. However, the biophysical mechanisms underlying the complex kinetics of growing axons remain elusive. Here, we develop a theoretical framework to recapitulate force-regulated states and their transitions in growing axons. We demonstrate a unique negative feedback mechanism that defines four distinct kinetic states in a growing axon, whose transitional boundaries depend on the interplay between cytoskeletal dynamics and axon-substrate adhesion. A phase diagram for axonal growth is formulated based on two dimensionless numbers.
... Neurons in the adult brain make precise connections between each other to form the appropriate neural circuits required for proper brain function [1,2]. During early postnatal development, such neural connectivity is first established by genetic programs and intrinsic activity [3]. ...
Early sensory experiences interact with genes to shape precise neural circuits during development. This process is vital for proper brain function in adulthood. Neurological dysfunctions caused by environmental alterations and/or genetic mutation may share the same molecular or cellular mechanisms. Here, we show that early life bilateral whisker trimming (BWT) subsequently affects social discrimination in adult male mice. Enhanced activation of the hippocampal dorsal CA3 (dCA3) in BWT mice was observed during social preference tests. Optogenetic activation of dCA3 in naive mice impaired social discrimination, whereas chemogenetic silencing of dCA3 rescued social discrimination deficit in BWT mice. Hippocampal oxytocin (OXT) is reduced after whisker trimming. Neonatal intraventricular compensation of OXT relieved dCA3 over-activation and prevented social dysfunction. Neonatal knockdown of OXT receptor in dCA3 mimics the effects of BWT, and cannot be rescued by OXT treatment. Social behavior deficits in a fragile X syndrome mouse model (Fmr1 KO mice) could also be recovered by early life OXT treatment, through negating dCA3 over-activation. Here, a possible avenue to prevent social dysfunction is uncovered.
... Axonal behavior is regulated by surface molecules that controls the degree of fasciculation processes and the integration of short and long-range signals that guide the growing axons toward their final targets. 17,43,44 The fr is a tightly packed tract originated in the habenular complex. Its fibers are segregated in a core region with axons from the mHb and a shell area with axons from the lHb. ...
Background
The fasciculus retroflexus is the prominent efferent pathway from the habenular complex. Medial habenular axons form a core packet whereas lateral habenular axons course in a surrounding shell. Both groups of fibers share the same initial pathway but differ in the final segment of the tract, supposedly regulated by surface molecules. The gene Amigo2 codes for a membrane adhesion molecule with an immunoglobulin‐like domain 2 and is selectively expressed in the medial habenula. We present it as a candidate for controlling the fasciculation behavior of medial habenula axons.
Results
First, we studied the development of the habenular efferents in an Amigo2 lack of function mouse model. The fasciculus retroflexus showed a variable defasciculation phenotype. Gain of function experiments allowed us to generate a more condensed tract and rescued the Amigo2 knock‐out phenotype. Changes in Amigo2 function did not alter the course of habenular fibers.
Conclusion
We have demonstrated that Amigo2 plays a subtle role in the fasciculation of the fasciculus retroflexus.
... Fine-tuned regulation of these connections is crucial for the accurate functioning of the network. Neuronal connectivity is established during development by linked processes of axon specification, outgrowth/ navigation, synapse formation and pruning of exuberant connections and undergoes limited remodelling in the mature central nervous system [1,2]. Consequently, ectopic, exuberant or imprecise connections can lead to major neurodevelopmental disorders [3][4][5][6]. ...
The establishment of neuronal connectivity relies on the microtubule (MT) cytoskeleton, which provides mechanical support, roads for axonal transport and mediates signalling events. Fine-tuned spatiotemporal regulation of MT functions by tubulin post-translational modifications and MT-associated proteins is critical for the coarse wiring and subsequent refinement of neuronal connectivity. The defective regulation of these processes causes a wide range of neurodevelopmental disorders associated with connectivity defects. This review focuses on recent studies unravelling how MT composition, post-translational modifications and associated proteins influence MT functions in axon guidance and/or pruning to build functional neuronal circuits. We here summarise experimental evidence supporting the key role of this network as a driving force for growth cone steering and branch-specific axon elimination. We further provide a global overview of the MT-interactors that tune developing axon behaviours, with a special emphasis on their emerging versatility in the regulation of MT dynamics/structure. Recent studies establishing the key and highly selective role of the tubulin code in the regulation of MT functions in axon pathfinding are also reported. Finally, our review highlights the emerging molecular links between these MT regulation processes and guidance signals that wire the nervous system.
... The vulnerability issue was reviewed by Back [96] for preterm brain and its great susceptibility to cerebral white matter injury disrupting the normal progression of developmental myelination. Tracts form along the path traced by the "pioneer axons", which are guided by various molecular cues [97]. This is an example of a highly precise phenomenon, during which any disturbance can have serious consequences in postnatal life. ...
Anthropogenic ultrafine particulate matter (UFPM) and industrial and natural nanoparticles (NPs) are ubiquitous. Normal term, preeclamptic, and postconceptional weeks(PCW) 8–15 human placentas and brains from polluted Mexican cities were analyzed by TEM and energy-dispersive X-ray spectroscopy. We documented NPs in maternal erythrocytes, early syncytiotrophoblast, Hofbauer cells, and fetal endothelium (ECs). Fetal ECs exhibited caveolar NP activity and widespread erythroblast contact. Brain ECs displayed micropodial extensions reaching luminal NP-loaded erythroblasts. Neurons and primitive glia displayed nuclear, organelle, and cytoplasmic NPs in both singles and conglomerates. Nanoscale Fe, Ti, and Al alloys, Hg, Cu, Ca, Sn, and Si were detected in placentas and fetal brains. Preeclamptic fetal blood NP vesicles are prospective neonate UFPM exposure biomarkers. NPs are reaching brain tissues at the early developmental PCW 8–15 stage, and NPs in maternal and fetal placental tissue compartments strongly suggests the placental barrier is not limiting the access of environmental NPs. Erythroblasts are the main early NP carriers to fetal tissues. The passage of UFPM/NPs from mothers to fetuses is documented and fingerprinting placental single particle composition could be useful for postnatal risk assessments. Fetal brain combustion and industrial NPs raise medical concerns about prenatal and postnatal health, including neurological and neurodegenerative lifelong consequences.
