Denis Jabaudon

SOX5 Controls the Sequential Generation of Distinct Corticofugal Neuron Subtypes

The molecular mechanisms controlling the development of distinct subtypes of neocortical projection neurons, and CNS neuronal diversity more broadly, are only now emerging. We report that the transcription factor SOX5 controls the sequential generation of distinct corticofugal neuron subtypes by preventing premature emergence of normally later-born corticofugal neurons. SOX5 loss-of-function causes striking overlap of the identities of the three principal sequentially born corticofugal neuron subtypes: subplate neurons, corticothalamic neurons, and subcerebral projection neurons. In Sox5(-/-) cortex, subplate neurons aberrantly develop molecular hallmarks and connectivity of subcerebral projection neurons; corticothalamic neurons are imprecisely differentiated, while differentiation of subcerebral projection neurons is accelerated. Gain-of-function analysis reinforces the critical role of SOX5 in controlling the sequential generation of corticofugal neurons--SOX5 overexpression at late stages of corticogenesis causes re-emergence of neurons with corticofugal features. These data indicate that SOX5 controls the timing of critical fate decisions during corticofugal neuron production and thus subtype-specific differentiation and neocortical neuron diversity.The molecular mechanisms controlling the development of distinct subtypes of neocortical projection neurons, and CNS neuronal diversity more broadly, are only now emerging. We report that the transcription factor SOX5 controls the sequential generation of distinct corticofugal neuron subtypes by preventing premature emergence of normally later-born corticofugal neurons. SOX5 loss-of-function causes striking overlap of the identities of the three principal sequentially born corticofugal neuron subtypes: subplate neurons, corticothalamic neurons, and subcerebral projection neurons. In Sox5(-/-) cortex, subplate neurons aberrantly develop molecular hallmarks and connectivity of subcerebral projection neurons; corticothalamic neurons are imprecisely differentiated, while differentiation of subcerebral projection neurons is accelerated. Gain-of-function analysis reinforces the critical role of SOX5 in controlling the sequential generation of corticofugal neurons--SOX5 overexpression at late stages of corticogenesis causes re-emergence of neurons with corticofugal features. These data indicate that SOX5 controls the timing of critical fate decisions during corticofugal neuron production and thus subtype-specific differentiation and neocortical neuron diversity.

Ctip2 Controls the Differentiation of Medium Spiny Neurons and the Establishment of the Cellular Architecture of the Striatum

Striatal medium spiny neurons (MSN) are critically involved in motor control, and their degeneration is a principal component of Huntingtons disease. We find that the transcription factor Ctip2 (also known as Bcl11b) is central to MSN differentiation and striatal development. Within the striatum, it is expressed by all MSN, although it is excluded from essentially all striatal interneurons. In the absence of Ctip2, MSN do not fully differentiate, as demonstrated by dramatically reduced expression of a large number of MSN markers, including DARPP-32, FOXP1, Chrm4, Reelin, MOR1 (μ-opioid receptor 1), glutamate receptor 1, and Plexin-D1. Furthermore, MSN fail to aggregate into patches, resulting in severely disrupted patch-matrix organization within the striatum. Finally, heterotopic cellular aggregates invade the Ctip2−/− striatum, suggesting a failure by MSN to repel these cells in the absence of Ctip2. This is associated with abnormal dopaminergic innervation of the mutant striatum and dramatic changes in gene expression, including dysregulation of molecules involved in cellular repulsion. Together, these data indicate that Ctip2 is a critical regulator of MSN differentiation, striatal patch development, and the establishment of the cellular architecture of the striatum.

SOX6 controls dorsal progenitor identity and interneuron diversity during neocortical development

The neuronal diversity of the CNS emerges largely from controlled spatial and temporal segregation of cell type-specific molecular regulators. We found that the transcription factor SOX6 controls the molecular segregation of dorsal (pallial) from ventral (subpallial) telencephalic progenitors and the differentiation of cortical interneurons, regulating forebrain progenitor and interneuron heterogeneity. During corticogenesis in mice, SOX6 and SOX5 were largely mutually exclusively expressed in pallial and subpallial progenitors, respectively, and remained mutually exclusive in a reverse pattern in postmitotic neuronal progeny. Loss of SOX6 from pallial progenitors caused their inappropriate expression of normally subpallium-restricted developmental controls, conferring mixed dorsal-ventral identity. In postmitotic cortical interneurons, loss of SOX6 disrupted the differentiation and diversity of cortical interneuron subtypes, analogous to SOX5 control over cortical projection neuron development. These data indicate that SOX6 is a central regulator of both progenitor and cortical interneuron diversity during neocortical development.

In vivo reprogramming of circuit connectivity in postmitotic neocortical neurons

The molecular mechanisms that control how progenitors generate distinct subtypes of neurons, and how undifferentiated neurons acquire their specific identity during corticogenesis, are increasingly understood. However, whether postmitotic neurons can change their identity at late stages of differentiation remains unknown. To study this question, we developed an electrochemical in vivo gene delivery method to rapidly manipulate gene expression specifically in postmitotic neurons. Using this approach, we found that the molecular identity, morphology, physiology and functional input-output connectivity of layer 4 mouse spiny neurons could be specifically reprogrammed during the first postnatal week by ectopic expression of the layer 5B output neuron–specific transcription factor Fezf2. These findings reveal a high degree of plasticity in the identity of postmitotic neocortical neurons and provide a proof of principle for postnatal re-engineering of specific neural microcircuits in vivo.

Area-specific temporal control of corticospinal motor neuron differentiation by COUP-TFI

Transcription factors with gradients of expression in neocortical progenitors give rise to distinct motor and sensory cortical areas by controlling the area-specific differentiation of distinct neuronal subtypes. However, the molecular mechanisms underlying this area-restricted control are still unclear. Here, we show that COUP-TFI controls the timing of birth and specification of corticospinal motor neurons (CSMN) in somatosensory cortex via repression of a CSMN differentiation program. Loss of COUP-TFI function causes an area-specific premature generation of neurons with cardinal features of CSMN, which project to subcerebral structures, including the spinal cord. Concurrently, genuine CSMN differentiate imprecisely and do not project beyond the pons, together resulting in impaired skilled motor function in adult mice with cortical COUP-TFI loss-of-function. Our findings indicate that COUP-TFI exerts critical areal and temporal control over the precise differentiation of CSMN during corticogenesis, thereby enabling the area-specific functional features of motor and sensory areas to arise.

Sequential transcriptional waves direct the differentiation of newborn neurons in the mouse neocortex

Tracking neuronal transcriptional programs Early in brain development, cortical neurons are born near the ventricles, then migrate to their functional destinations. Telley et al. used a fluorescent labeling technique to see what transcripts characterize these earliest stages of neural development. Waves of transcriptional programs are initiated, then passed by as the neuron progresses from proliferative to migratory and finally to connectivity phases. Science, this issue p. 1443 In vivo fluorescence labeling reveals neuron-specific primordial transcriptional programs as they dynamically unfold. During corticogenesis, excitatory neurons are born from progenitors located in the ventricular zone (VZ), from where they migrate to assemble into circuits. How neuronal identity is dynamically specified upon progenitor division is unknown. Here, we study this process using a high-temporal-resolution technology allowing fluorescent tagging of isochronic cohorts of newborn VZ cells. By combining this in vivo approach with single-cell transcriptomics in mice, we identify and functionally characterize neuron-specific primordial transcriptional programs as they dynamically unfold. Our results reveal early transcriptional waves that instruct the sequence and pace of neuronal differentiation events, guiding newborn neurons toward their final fate, and contribute to a road map for the reverse engineering of specific classes of cortical neurons from undifferentiated cells.

Unveiling the diversity of thalamocortical neuron subtypes

Our current understanding of thalamocortical (TC) circuits is largely based on studies investigating so‐called ‘specific’ thalamic nuclei, which receive and transmit sensory‐triggered input to specific cortical target areas. TC neurons in these nuclei have a striking point‐to‐point topography and a stereotyped laminar pattern of termination in the cortex, which has made them ideal models to study the organization, plasticity, and development of TC circuits. However, despite their experimental importance, neurons within these nuclei only represent a fraction of all thalamic neurons and do not reflect the diversity of the TC neuron population. Here we review the distinct subtypes of projection neurons that populate the thalamus, both within and across anatomically‐defined nuclei, with regard to differences in their morphology, input/output connectivity and target specificity, as well as more recent findings on their neuron type‐specific gene expression and development. We argue that a detailed understanding of the biology of TC neurons is critical to understand the role of the thalamus in normal and pathological perception, voluntary movement, cognition and attention.

Modality-specific thalamocortical inputs instruct the identity of postsynaptic L4 neurons

During development, thalamocortical (TC) input has a critical role in the spatial delineation and patterning of cortical areas, yet the underlying cellular and molecular mechanisms that drive cortical neuron differentiation are poorly understood. In the primary (S1) and secondary (S2) somatosensory cortex, layer 4 (L4) neurons receive mutually exclusive input originating from two thalamic nuclei: the ventrobasalis (VB), which conveys tactile input, and the posterior nucleus (Po), which conveys modulatory and nociceptive input. Recently, we have shown that L4 neuron identity is not fully committed postnatally, implying a capacity for TC input to influence differentiation during cortical circuit assembly. Here we investigate whether the cell-type-specific molecular and functional identity of L4 neurons is instructed by the origin of their TC input. Genetic ablation of the VB at birth resulted in an anatomical and functional rewiring of Po projections onto L4 neurons in S1. This induced acquisition of Po input led to a respecification of postsynaptic L4 neurons, which developed functional molecular features of Po-target neurons while repressing VB-target traits. Respecified L4 neurons were able to respond both to touch and to noxious stimuli, in sharp contrast to the normal segregation of these sensory modalities in distinct cortical circuits. These findings reveal a behaviourally relevant TC-input-type-specific control over the molecular and functional differentiation of postsynaptic L4 neurons and cognate intracortical circuits, which instructs the development of modality-specific neuronal and circuit properties during corticogenesis.

RORβ Induces Barrel-like Neuronal Clusters in the Developing Neocortex

Neurons in layer IV of the rodent whisker somatosensory cortex are tangentially organized in periodic clusters called barrels, each of which is innervated by thalamocortical axons transmitting sensory information from a single principal whisker, together forming a somatotopic map of the whisker pad. Proper thalamocortical innervation is critical for barrel formation during development, but the molecular mechanisms controlling layer IV neuron clustering are unknown. Here, we investigate the role in this mapping of the nuclear orphan receptor RORβ, which is expressed in neurons in layer IV during corticogenesis. We find that RORβ protein expression specifically increases in the whisker barrel cortex during barrel formation and that in vivo overexpression of RORβ is sufficient to induce periodic barrel-like clustering of cortical neurons. Remarkably, this clustering can be induced as early as E18, prior to innervation by thalamocortical afferents and whisker derived-input. At later developmental stages, these ectopic neuronal clusters are specifically innervated by thalamocortical axons, demonstrated by anterograde labeling from the thalamus and by expression of thalamocortical-specific synaptic markers. Together, these data indicate that RORβ expression levels control cytoarchitectural patterning of neocortical neurons during development, a critical process for the topographical mapping of whisker input onto the cortical surface.

Retinal Input Directs the Recruitment of Inhibitory Interneurons into Thalamic Visual Circuits

Inhibitory interneurons (INs) critically control the excitability and plasticity of neuronal networks, but whether activity can direct INs into specific circuits during development is unknown. Here, we report that in the dorsal lateral geniculate nucleus (dLGN), which relays retinal input to the cortex, circuit activity is required for the migration, molecular differentiation, and functional integration of INs. We first characterize the prenatal origin and molecular identity of dLGN INs, revealing their recruitment from an Otx2(+) neuronal pool located in the adjacent ventral LGN. Using time-lapse and electrophysiological recordings, together with genetic and pharmacological perturbation of retinal waves, we show that retinal activity directs the navigation and circuit incorporation of dLGN INs during the first postnatal week, thereby regulating the inhibition of thalamocortical circuits. These findings identify an input-dependent mechanism regulating IN migration and circuit inhibition, which may account for the progressive recruitment of INs into expanding excitatory circuits during evolution.