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Molecular Neurobiology Aug 2022WD-repeat domain 5 (WDR5), a core component of histone methyltransferase complexes, is associated with Kabuki syndrome and Kleefstra syndrome that feature intellectual...
WD-repeat domain 5 (WDR5), a core component of histone methyltransferase complexes, is associated with Kabuki syndrome and Kleefstra syndrome that feature intellectual disability and neurodevelopmental delay. Despite its critical status in gene regulation and neurological disorders, the role of WDR5 in neural development is unknown. Here we show that WDR5 is required for normal neuronal placement and dendrite polarization in the developing cerebral cortex. WDR5 knockdown led to defects in both entry into the bipolar transition of pyramidal neurons within the intermediate zone and radial migration into cortical layers. Moreover, WDR5 deficiency disrupted apical and basal polarity of cortical dendrites. Aberrant dendritic spines and synapses accompanied the dendrite polarity phenotype. WDR5 deficiency reduced expression of reelin signaling receptors, ApoER and VdldR, which were associated with abnormal H3K4 methylation and H4 acetylation on their promoter regions. Finally, an lncRNA, HOTTIP, was found to be a partner of WDR5 to regulate dendritic polarity and reelin signaling via histone modification. Our results demonstrate a novel role for WDR5 in neuronal development and provide mechanistic insights into the neuropathology associated with histone methyltransferase dysfunction.
Topics: Dendrites; Histone Methyltransferases; Histones; Neurogenesis; Pyramidal Cells
PubMed: 35672601
DOI: 10.1007/s12035-022-02905-4 -
Molecular Biology of the Cell Oct 2023Nervous systems exhibit dramatic diversity in cell morphology and size. How neurons regulate their biosynthetic and secretory machinery to support such diversity is not...
Nervous systems exhibit dramatic diversity in cell morphology and size. How neurons regulate their biosynthetic and secretory machinery to support such diversity is not well understood. Endoplasmic reticulum exit sites (ERESs) are essential for maintaining secretory flux, and are required for normal dendrite development, but how neurons of different size regulate secretory capacity remains unknown. In , we find that the ERES number is strongly correlated with the size of a neuron's dendritic arbor. The elaborately branched sensory neuron, PVD, has especially high ERES numbers. Asymmetric cell division provides PVD with a large initial cell size critical for rapid establishment of PVD's high ERES number before neurite outgrowth, and these ERESs are maintained throughout development. Maintenance of ERES number requires the cell fate transcription factor MEC-3, TOR (), and nutrient availability, with and mutant PVDs both displaying reductions in ERES number, soma size, and dendrite size. Notably, mutant animals exhibit reduced expression of a reporter in PVD, and starvation reduces ERES number and somato-dendritic size in a manner genetically redundant with perturbation. Our data suggest that both asymmetric cell division and nutrient sensing pathways regulate secretory capacities to support elaborate dendritic arbors.
Topics: Animals; Caenorhabditis elegans; Sensory Receptor Cells; Caenorhabditis elegans Proteins; Biological Transport; Endoplasmic Reticulum; Dendrites
PubMed: 37556208
DOI: 10.1091/mbc.E23-03-0090 -
Neuroscience May 2022Microtubules deliver essential resources to and from synapses. Three-dimensional reconstructions in rat hippocampus reveal a sampling bias regarding spine density that...
Microtubules deliver essential resources to and from synapses. Three-dimensional reconstructions in rat hippocampus reveal a sampling bias regarding spine density that needs to be controlled for dendrite caliber and resource delivery based on microtubule number. The strength of this relationship varies across dendritic arbors, as illustrated for area CA1 and dentate gyrus. In both regions, proximal dendrites had more microtubules than distal dendrites. For CA1 pyramidal cells, spine density was greater on thicker than thinner dendrites in stratum radiatum, or on the more uniformly thin terminal dendrites in stratum lacunosum moleculare. In contrast, spine density was constant across the cone shaped arbor of tapering dendrites from dentate granule cells. These differences suggest that thicker dendrites supply microtubules to subsequent dendritic branches and local dendritic spines, whereas microtubules in thinner dendrites need only provide resources to local spines. Most microtubules ran parallel to dendrite length and associated with long, presumably stable mitochondria, which occasionally branched into lateral dendritic branches. Short, presumably mobile, mitochondria were tethered to microtubules that bent and appeared to direct them into a thin lateral branch. Prior work showed that dendritic segments with the same number of microtubules had elevated resources in subregions of their dendritic shafts where spine synapses had enlarged, and spine clusters had formed. Thus, additional microtubules were not required for redistribution of resources locally to growing spines or synapses. These results provide new understanding about the potential for microtubules to regulate resource delivery to and from dendritic branches and locally among dendritic spines.
Topics: Animals; Dendrites; Dendritic Spines; Hippocampus; Microtubules; Pyramidal Cells; Rats; Synapses
PubMed: 35218884
DOI: 10.1016/j.neuroscience.2022.02.021 -
Journal of Cell Science Jul 2019Protein palmitoylation is the most common post-translational lipid modification in the brain and is mediated by a family of 24 zDHHC enzymes. There has been growing...
Protein palmitoylation is the most common post-translational lipid modification in the brain and is mediated by a family of 24 zDHHC enzymes. There has been growing interest in zDHHCs due to mounting evidence that these enzymes play key roles in the development and function of neuronal connections, and the fact that a number of zDHHCs have been associated with neurodevelopmental and neurodegenerative diseases. Loss-of-function variants in several zDHHCs, including zDHHC15, have been identified in patients with intellectual disabilities; however, the function of zDHHC15 in the brain has not been well studied. Here, we demonstrate that knocking down zDHHC15 in primary rat hippocampal cultures reduces dendritic outgrowth and arborization, as well as spine maturation. Moreover, knockdown of zDHHC15 reduces palmitoylation of PSD-95 and its trafficking into dendrites, resulting in an overall decrease in the density of excitatory synapses being formed onto mutant cells.
Topics: Acyltransferases; Animals; DNA-Binding Proteins; Dendrites; Dendritic Spines; Disks Large Homolog 4 Protein; Golgi Apparatus; HEK293 Cells; Hippocampus; Humans; Mice; Rats, Sprague-Dawley; Synapses
PubMed: 31189538
DOI: 10.1242/jcs.230052 -
Molecular Neurobiology Apr 2004For more than a century dendritic spines have been a source of fascination and speculation. The long-held belief that these anatomical structures are involved in... (Review)
Review
For more than a century dendritic spines have been a source of fascination and speculation. The long-held belief that these anatomical structures are involved in learning and memory are addressed. Specifically, two lines of evidence that support this claim are reviewed. In the first, we review evidence that experimental manipulations that affect dendritic spine number in the hippocampus also affect learning processes of various sorts. In the second, we review evidence that learning itself affects the presence of dendritic spines in the hippocampus. Based on these observations, we propose that the presence of spines enhances synaptic efficacy and thereby the excitability of the network involved in the learning process. With this scheme, learning is not dependent on changes in spine density but rather changes in the presence of dendritic spines provide anatomical support for the processing of novel information used in memory formation.
Topics: Animals; Dendrites; Estrogens; Humans; Memory; Neuronal Plasticity
PubMed: 15126680
DOI: 10.1385/MN:29:2:117 -
Neuroscience Bulletin Nov 2022The back-propagating action potential (bpAP) is crucial for neuronal signal integration and synaptic plasticity in dendritic trees. Its properties (velocity and...
The back-propagating action potential (bpAP) is crucial for neuronal signal integration and synaptic plasticity in dendritic trees. Its properties (velocity and amplitude) can be affected by dendritic morphology. Due to limited spatial resolution, it has been difficult to explore the specific propagation process of bpAPs along dendrites and examine the influence of dendritic morphology, such as the dendrite diameter and branching pattern, using patch-clamp recording. By taking advantage of Optopatch, an all-optical electrophysiological method, we made detailed recordings of the real-time propagation of bpAPs in dendritic trees. We found that the velocity of bpAPs was not uniform in a single dendrite, and the bpAP velocity differed among distinct dendrites of the same neuron. The velocity of a bpAP was positively correlated with the diameter of the dendrite on which it propagated. In addition, when bpAPs passed through a dendritic branch point, their velocity decreased significantly. Similar to velocity, the amplitude of bpAPs was also positively correlated with dendritic diameter, and the attenuation patterns of bpAPs differed among different dendrites. Simulation results from neuron models with different dendritic morphology corresponded well with the experimental results. These findings indicate that the dendritic diameter and branching pattern significantly influence the properties of bpAPs. The diversity among the bpAPs recorded in different neurons was mainly due to differences in dendritic morphology. These results may inspire the construction of neuronal models to predict the propagation of bpAPs in dendrites with enormous variation in morphology, to further illuminate the role of bpAPs in neuronal communication.
Topics: Action Potentials; Dendrites; Neurons; Neuronal Plasticity; Pyramidal Cells
PubMed: 35984622
DOI: 10.1007/s12264-022-00931-9 -
ELife Nov 2019Patterns of synaptic connectivity are remarkably precise and complex. Single-cell RNA sequencing has revealed a vast transcriptional diversity of neurons. Nevertheless,...
Patterns of synaptic connectivity are remarkably precise and complex. Single-cell RNA sequencing has revealed a vast transcriptional diversity of neurons. Nevertheless, a clear logic underlying the transcriptional control of neuronal connectivity has yet to emerge. Here, we focused on T4/T5 neurons, a class of closely related neuronal subtypes with different wiring patterns. Eight subtypes of T4/T5 neurons are defined by combinations of two patterns of dendritic inputs and four patterns of axonal outputs. Single-cell profiling during development revealed distinct transcriptional programs defining each dendrite and axon wiring pattern. These programs were defined by the expression of a few transcription factors and different combinations of cell surface proteins. Gain and loss of function studies provide evidence for independent control of different wiring features. We propose that modular transcriptional programs for distinct wiring features are assembled in different combinations to generate diverse patterns of neuronal connectivity.
Topics: Animals; Axons; Cells, Cultured; Dendrites; Drosophila; Gene Expression Regulation; Neural Conduction; Single-Cell Analysis; Transcription, Genetic
PubMed: 31687928
DOI: 10.7554/eLife.50822 -
Neuron Jan 2002The cellular and molecular mechanisms that guide axonal and dendritic differentiation in the cerebral cortex are just beginning to be defined. Many of the molecular... (Review)
Review
The cellular and molecular mechanisms that guide axonal and dendritic differentiation in the cerebral cortex are just beginning to be defined. Many of the molecular signals that guide axons also, and sometimes simultaneously, influence dendritic growth. Whitford et al. (2002 [this issue of Neuron]) demonstrate that in addition to their roles in axon guidance and cell migration cue, Slit proteins can also regulate dendritic growth.
Topics: Animals; Carrier Proteins; Cell Differentiation; Cerebral Cortex; Chemotaxis; Dendrites; Growth Cones; Humans; Nerve Tissue Proteins; Receptors, Immunologic; Semaphorin-3A; Roundabout Proteins
PubMed: 11779471
DOI: 10.1016/s0896-6273(01)00577-3 -
Developmental Biology Oct 2016The size and shape of dendrite arbors are defining features of neurons and critical determinants of neuronal function. The molecular mechanisms establishing arborization...
The size and shape of dendrite arbors are defining features of neurons and critical determinants of neuronal function. The molecular mechanisms establishing arborization patterns during development are not well understood, though properly regulated microtubule (MT) dynamics and polarity are essential. We previously found that FoxO regulates axonal MTs, raising the question of whether it also regulates dendritic MTs and morphology. Here we demonstrate that FoxO promotes dendrite branching in all classes of Drosophila dendritic arborization (da) neurons. FoxO is required both for initiating growth of new branches and for maintaining existing branches. To elucidate FoxO function, we characterized MT organization in both foxO null and overexpressing neurons. We find that FoxO directs MT organization and dynamics in dendrites. Moreover, it is both necessary and sufficient for anterograde MT polymerization, which is known to promote dendrite branching. Lastly, FoxO promotes proper larval nociception, indicating a functional consequence of impaired da neuron morphology in foxO mutants. Together, our results indicate that FoxO regulates dendrite structure and function and suggest that FoxO-mediated pathways control MT dynamics and polarity.
Topics: Animals; Dendrites; Drosophila; Drosophila Proteins; Forkhead Transcription Factors; Gene Expression Regulation, Developmental; Microtubules; Sensory Receptor Cells
PubMed: 27546375
DOI: 10.1016/j.ydbio.2016.08.018 -
Neuron Feb 2021The synaptotrophic hypothesis posits that synapse formation stabilizes dendritic branches, but this hypothesis has not been causally tested in vivo in the mammalian...
The synaptotrophic hypothesis posits that synapse formation stabilizes dendritic branches, but this hypothesis has not been causally tested in vivo in the mammalian brain. The presynaptic ligand cerebellin-1 (Cbln1) and postsynaptic receptor GluD2 mediate synaptogenesis between granule cells and Purkinje cells in the molecular layer of the cerebellar cortex. Here we show that sparse but not global knockout of GluD2 causes under-elaboration of Purkinje cell dendrites in the deep molecular layer and overelaboration in the superficial molecular layer. Developmental, overexpression, structure-function, and genetic epistasis analyses indicate that these dendrite morphogenesis defects result from a deficit in Cbln1/GluD2-dependent competitive interactions. A generative model of dendrite growth based on competitive synaptogenesis largely recapitulates GluD2 sparse and global knockout phenotypes. Our results support the synaptotrophic hypothesis at initial stages of dendrite development, suggest a second mode in which cumulative synapse formation inhibits further dendrite growth, and highlight the importance of competition in dendrite morphogenesis.
Topics: Animals; Cerebellum; Dendrites; Female; Mice; Mice, Inbred ICR; Mice, Knockout; Mice, Transgenic; Nerve Tissue Proteins; Pregnancy; Protein Binding; Protein Precursors; Purkinje Cells; Receptors, Glutamate
PubMed: 33352118
DOI: 10.1016/j.neuron.2020.11.028