Her6 regulates the neurogenetic gradient and neuronal identity in the thalamus.
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ABSTRACT:
SUBMITTER: Scholpp S
PROVIDER: S-EPMC2775703 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundThe thalamus is often defined as the 'gateway to consciousness', a feature that is supported by the specific connectivity and electrophysiological properties of its neurons. Inhibitory GABAergic neurons are required for the dynamic gating of information passing through the thalamus. The high degree of heterogeneity among thalamic GABA neurons suggests that, during embryonic development, alternative differentiation programmes exist to guide the acquisition of inhibitory neuron subtype identity.ResultsTaking advantage of the accessibility of the developing chick embryo, we have used in ovo manipulations of gene expression to test the role of candidate transcription factors in controlling GABAergic neuronal subtype identity in the developing thalamus.ConclusionsIn this study, we describe two alternative differentiation programmes for GABAergic neurogenesis in the thalamus and identify Helt and Dlx2 as key transcription factors that are sufficient to direct neuronal progenitors along a specific differentiation pathway at the expense of alternative lineage choices. Furthermore, we identify Calb2, a gene encoding for the GABA subtype marker calretinin as a target of the transcription factor Sox14. This work is a step forward in our understanding of how GABA neuron diversity in the thalamus is achieved during development and will help future investigation of the molecular mechanisms that lead up to the acquisition of different synaptic targets and electrophysiological features of mature thalamic inhibitory neurons.
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Project description:Neural Hu proteins (HuB/C/D) are RNA-binding proteins that have been shown to induce neuronal differentiation activity when overexpressed in immature neural progenitor cells or undifferentiated neuronal tumors. Newly generated HuD-deficient mice exhibited a transient impaired-cranial-nerve-development phenotype at an early embryonic stage. Adult HuD-deficient mice exhibited an abnormal hind-limb reflex and poor rotarod performance. Analysis of neurosphere formation revealed that the number and self-renewal capacity of the neural stem/progenitor cells were increased in HuD-deficient mice. HuD-deficient primary neurospheres also generated a smaller number of neurons. Cohort analysis of the cellular proliferative activity by using BrdUrd and iododeoxuridine labeling revealed that the number of differentiating quiescent cells in the embryonic cerebral wall was decreased. Long-term administration of BrdUrd revealed that the number of slowly dividing stem cells in the adult subventricular zone was increased in the HuD-deficient mice. Taken together, the results suggest that HuD is required at multiple points during neuronal development, including negative regulation of proliferative activity and neuronal cell-fate acquisition of neural stem/progenitor cells.
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Project description:CCCTC-binding factor (CTCF) is a regulator of chromatin organization and has direct effects on gene transcription. Mutations in CTCF have been identified in individuals with neurodevelopmental conditions. There are wide range of behaviors associated with these mutations, including intellectual disabilities, changes in temperament, and autism. Previous mice-model studies have identified roles for CTCF in excitatory neurons in specific behaviors, particularly in regards to learning and memory. However, the role of CTCF in inhibitory neurons is less well defined. In the current study, specific knockout of CTCF in parvalbumin-expressing neurons, a subset of inhibitory neurons, induced a specific behavioral phenotype, including locomotor abnormalities, anxiolytic behavior, and a decrease in social behavior. The anxiolytic and social abnormalities are detected before the onset of locomotor abnormalities. Immunohistochemical analysis revealed a disbalance in parvalbumin-expressing and somatostatin-expressing cells in these mice. Single nuclei RNA sequencing identified changes in gene expression in parvalbumin-expressing neurons that are specific to inhibitory neuronal identity and function. Electrophysiology analysis revealed an enhanced inhibitory tone in the hippocampal pyramidal neurons in knockout mice. These findings indicate that CTCF in parvalbumin-expressing neurons has a significant role in the overall phenotype of CTCF-associated neurodevelopmental deficits.
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Project description:Learning reduces variability but variability can facilitate learning. This paradoxical relationship has made it challenging to tease apart sources of variability that degrade performance from those that improve it. We tackled this question in a context-dependent timing task requiring humans and monkeys to flexibly produce different time intervals with different effectors. We identified two opposing factors contributing to timing variability: slow memory fluctuation that degrades performance and reward-dependent exploratory behavior that improves performance. Signatures of these opposing factors were evident across populations of neurons in the dorsomedial frontal cortex (DMFC), DMFC-projecting neurons in the ventrolateral thalamus, and putative target of DMFC in the caudate. However, only in the thalamus were the performance-optimizing regulation of variability aligned to the slow performance-degrading memory fluctuations. These findings reveal how variability caused by exploratory behavior might help to mitigate other undesirable sources of variability and highlight a potential role for thalamocortical projections in this process.
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Project description:Neuronal diversity is an intrinsic feature of the nervous system. Transcription factors (TFs) are key regulators in the establishment of different neuronal identities; how are the actions of different TFs coordinated to orchestrate this diversity? Are there common features shared among the different neuron types of an organism or even among different animal groups? In this review, we provide a brief overview on common traits emerging on the transcriptional regulation of neuron type diversification with a special focus on the comparison between mouse and Caenorhabditis elegans model systems. In the first part, we describe general concepts on neuronal identity and transcriptional regulation of gene expression. In the second part of the review, TFs are classified in different categories according to their key roles at specific steps along the protracted process of neuronal specification and differentiation. The same TF categories can be identified both in mammals and nematodes. Importantly, TFs are very pleiotropic: Depending on the neuron type or the time in development, the same TF can fulfil functions belonging to different categories. Finally, we describe the key role of transcriptional repression at all steps controlling neuronal diversity and propose that acquisition of neuronal identities could be considered a metastable process.
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Project description:Stimulus specific adaptation has been studied extensively in different modalities. High specificity implies that deviant stimulus induces a stronger response compared to a common stimulus. The thalamus gates sensory information to the cortex, therefore, the specificity of adaptation in the thalamus must have a great impact on cortical processing of sensory inputs. We studied the specificity of adaptation to whisker identity in the ventral posteromedial nucleus of the thalamus (VPM) in rats using extracellular and intracellular recordings. We found that subsequent to repetitive stimulation that induced strong adaptation, the response to stimulation of the same, or any other responsive whisker was equally adapted, indicating that thalamic adaptation is non-specific. In contrast, adaptation of single units in the upstream brainstem principal trigeminal nucleus (PrV) was significantly more specific. Depolarization of intracellularly recorded VPM cells demonstrated that adaptation is not due to buildup of inhibition. In addition, adaptation increased the probability of observing complete synaptic failures to tactile stimulation. In accordance with short-term synaptic depression models, the evoked synaptic potentials in response to whisker stimulation, subsequent to a response failure, were facilitated. In summary, we show that local short-term synaptic plasticity is involved in the transformation of adaptation in the trigemino-thalamic synapse and that the low specificity of adaptation in the VPM emerges locally rather than cascades from earlier stages. Taken together we suggest that during sustained stimulation, local thalamic mechanisms equally suppress inputs arriving from different whiskers before being gated to the cortex.
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Project description:The projection neurons of the neocortex are produced in the pseudostratified ventricular epithelium (PVE) lining the embryonic lateral ventricles. Over a 7 d period in mouse, these neurons arise in an overlapping layer VI-to-II sequence and in an anterolateral to posteromedial gradient [the transverse neurogenetic gradient (TNG)]. At any time in the 7 d neurogenetic interval, a given PVE cell must know what class of precursor cell or neuron to form next. How this information is encoded in the PVE is not known. With comparative experiments in wild-type and double-transgenic mice, overexpressing the cell cycle inhibitor p27(Kip1), we show that a gradient of expression of Lhx2 (inferred from its mRNA levels), a LIM homeodomain transcription factor, together with a gradient in duration of the G1 phase of the cell cycle (T(G1)), are sufficient to specify a positional mapping system that informs the PVE cell what class of neuron to produce next. Lhx2 likely is representative of an entire class of transcription factors expressed along the TNG. This mapping system consisting of a combination of signals from two different sources is a novel perspective on the source of positional information for neuronal specification in the developing CNS.
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Project description:The transcriptional programs that establish neuronal identity evolved to produce the rich diversity of neuronal cell types that arise sequentially during development. Remarkably, transient expression of certain transcription factors can also endow non-neural cells with neuronal properties. The relationship between reprogramming factors and the transcriptional networks that produce neuronal identity and diversity remains largely unknown. Here, from a screen of 598 pairs of transcription factors, we identify 76 pairs of transcription factors that induce mouse fibroblasts to differentiate into cells with neuronal features. By comparing the transcriptomes of these induced neuronal cells (iN cells) with those of endogenous neurons, we define a 'core' cell-autonomous neuronal signature. The iN cells also exhibit diversity; each transcription factor pair produces iN cells with unique transcriptional patterns that can predict their pharmacological responses. By linking distinct transcription factor input 'codes' to defined transcriptional outputs, this study delineates cell-autonomous features of neuronal identity and diversity and expands the reprogramming toolbox to facilitate engineering of induced neurons with desired patterns of gene expression and related functional properties.
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