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.arealization | subcerebral projection neurons | neocortex development | corticofugal neurons | nuclear receptor | behavior T he mammalian cerebral cortex, responsible for fine motor control and sensorimotor integration, is subdivided into functionally distinct areas that control motor functions and process distinct sensory modalities (1). Individual areas are distinguished by their cytoarchitecture, connectivity, physiology, and patterns of gene expression (2, 3). Each area is radially divided into six layers, and each layer consists of a variety of populations of neurons with distinctive morphologies, connectivity, and developmental programs of gene expression (4-9). In particular, layers VI and V contain corticofugal neurons, which send their axons to deep brain structures, such as the thalamus (corticothalamic neurons), the striatum (corticostriatal neurons), pons (corticopontine neurons), tectum (corticotectal neurons), and spinal cord (corticospinal motor neurons, CSMN) (7).The fate of neurons and laminar cytoarchitecture in each specific area determines their function: the adult primary motor cortex contains a large number of CSMN and has a thick layer V; the primary somatosensory area is characterized by a thick layer IV, where the neurons that receive relayed sensory inputs are located (10). The area-specific differences in neuronal fate and cytoarchitecture have been thought to result from late postmitotic events, e.g. selective postnatal pruning of axons (11), and premitotic events, such as the timing, rate, and duration of proliferation of precursors producing distinct projection neuron subtypes (12-16). As a striking illustration of such processes, CSMN are generated at a higher rate in the developing motor cortex than in sensory areas in mice (12), but the molecular mechanisms that control this area-specific differential production of CSMN are not known. The transcription factor COUP-TFI is particularly interestin...

Mucopolysaccharidoses type IIIA (MPS-IIIA) is a neurodegenerative lysosomal storage disorder (LSD) caused by inherited defects of the sulphamidase gene. Here, we used a systemic gene transfer approach to demonstrate the therapeutic efficacy of a chimeric sulphamidase, which was engineered by adding the signal peptide (sp) from the highly secreted iduronate-2-sulphatase (IDS) and the blood-brain barrier (BBB)-binding domain (BD) from the Apolipoprotein B (ApoB-BD). A single intravascular administration of AAV2/8 carrying the modified sulphamidase was performed in adult MPS-IIIA mice in order to target the liver and convert it to a factory organ for sustained systemic release of the modified sulphamidase. We showed that while the IDS sp replacement results in increased enzyme secretion, the addition of the ApoB-BD allows efficient BBB transcytosis and restoration of sulphamidase activity in the brain of treated mice. This, in turn, resulted in an overall improvement of brain pathology and recovery of a normal behavioural phenotype. Our results provide a novel feasible strategy to develop minimally invasive therapies for the treatment of brain pathology in MPS-IIIA and other neurodegenerative LSDs.

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