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During cerebral cortex development, excitatory pyramidal neurons (PNs) establish specific projection patterns while receiving inputs from GABAergic inhibitory interneurons (INs). Whether these inhibitory inputs can shape PNs' projection patterns is, however, unknown. While layer 4 (L4) PNs of the primary somatosensory (S1) cortex are all born as long-range callosal projection neurons (CPNs), most of them acquire local connectivity upon activity-dependent elimination of their interhemispheric axons during postnatal development. Here, we demonstrate that precise developmental regulation of inhibition is key for the retraction of S1L4 PNs' callosal projections. Ablation of somatostatin INs leads to premature inhibition from parvalbumin INs onto S1L4 PNs and prevents them from acquiring their barrel-restricted local connectivity pattern. As a result, adult S1L4 PNs retain interhemispheric projections responding to tactile stimuli, and the mice lose whisker-based texture discrimination. Overall, we show that temporally ordered IN activity during development is key to shaping local ipsilateral S1L4 PNs' projection pattern, which is required for fine somatosensory processing.

Whereas neurons of the lower layers (VI-V) of the cerebral cortex are first born from dividing precursors at the ventricular zone, upper layer neurons (II-IV) subsequently arise from divisions of intermediate neuronal precursors at the subventricular zone (SVZ). Little is known about mechanisms that control the proliferation of SVZ neuronal precursors. We herein report that the restricted expression of the homeodomain transcription factor Cux-2 in the SVZ regulates the proliferation of intermediate neuronal precursors and the number of upper layer neurons. In Cux-2-deficient mice (Cux-2-/-), there is excessive number of upper layer neurons and selective expansion of SVZ neuronal precursors. Double-labeling experiments demonstrate that Cux-2-/- upper layer precursors reenter the cell cycle in a higher frequency than wild-type precursors. Overexpression studies indicate that Cux-2 controls cell cycle exit in a cell-autonomous manner. Analysis of Cux-1-/-; Cux-2-/- double mutant revealed that Cux-2 controls SVZ proliferation independently of Cux-1, demonstrating that this is a unique function of Cux-2, not redundant with Cux-1 activities. Our results point to Cux-2 as a key element in the control of the proliferation rates of the SVZ precursors and the number of upper cortical neurons, without altering the number of deep cortical layers., Depto. de Bioquímica y Biología Molecular, Fac. de Medicina, TRUE, pub

Homeodomain transcription factors play important roles in the specification and differentiation of neuronal subpopulations. In the cerebral cortex, the expression patterns of Cux‐1 and Cux‐2 in the medial ganglionic eminence (MGE) suggest a role for these transcription factors in the development of interneurons, a heterogeneous neuronal population. In this report, we describe expression of Cux‐1 and Cux‐2 proteins in Reelin‐secreting interneurons of the cortical plate, but not in calretinin or parvalbumin subpopulations. The role of Cux genes in the development of Reelin positive neurons was studied using Cux‐1 and Cux‐2 knockout mice. These experiments demonstrate that Cux‐1−/−; Cux‐2−/− double mutation is embryonically lethal. Although this phenotype is highly penetrant, a small proportion of mice develop to birth (P0). Analysis of these animals demonstrate that expression of Reelin is completely absent in layers II–IV of Cux‐1−/−; Cux‐2−/− double mutant mice, but it is not affected in the cortex of Cux‐1−/− or Cux‐2−/− single mutants. No Cux‐1−/−; Cux‐2−/− double‐mutant were collected after P0. Since, GABA‐ergic populations mature at late postnatal stages, this did not allow us to analyze the expression of subclass specific markers and define the affected interneuron subpopulations. Our analysis of Cux‐1−/−; Cux‐2−/− double mutant thus demonstrates essential yet redundant roles for Cux‐1 and Cux‐2 in specifying Reelin expressing cortical interneurons. © 2008 Wiley Periodicals, Inc. Develop Neurobiol, 2008., Depto. de Bioquímica y Biología Molecular, Fac. de Medicina, TRUE, pub

Aim Anastomotic leakage (AL) following ileorectal (IRA) or ileosigmoid (ISA) anastomosis is associated with a high morbidity. The identification of potential risk factors for AL could change operative planning and reduce further complications. This study assesses the rate, potential risk factors and management of AL after total colectomy (TC) and subtotal colectomy (STC). Methods A nationwide, multicentre, retrospective cohort study involved 26 Spanish referral centres. It included TC and STC with IRA or ISA patients between January 2013 and December 2020. Clinical data, primary surgery and complications were collected. Univariate and multivariate analysis to identify risk factors for AL were performed. Management of Grade B–C AL and permanent stoma rate was assessed according to revisional surgeries. Results The study included 1074 patients, 433 ISA group (40.3%) and 641 IRA group (59.7%). The overall incidence of AL was 14.3% with no differences between IRA and ISA (14.2% and 14.5% respectively), P = 0.871. Male sex, ASA score and lower total preoperative proteins were identified as independent risk factors for global and Grade B–C AL. Diverting ileostomy did not protect against AL (P = 0.084). Clavien–Dindo ≥IIIA complication was found in 251 patients (23.3%). Stoma reversal was not possible in 85 patients (8.1%), being more frequent after anastomosis excision and terminal ileostomy in AL Grade C. Conclusion Total colectomy and STC with IRA or ISA are high-risk procedures with an increased AL rate. Male sex, ASA score and lower preoperative protein level were associated with global AL and AL Grade B and C. A lower permanent stoma rate could be obtained when diverting ileostomy is performed in revision surgery., Depto. de Cirugía, Fac. de Medicina, TRUE, pub

Dendrite branching and spine formation determines the function of morphologically distinct and specialized neuronal subclasses. However, little is known about the programs instructing specific branching patterns in vertebrate neurons and whether such programs influence dendritic spines and synapses. Using knockout and knockdown studies combined with morphological, molecular, and electrophysiological analysis, we show that the homeobox Cux1 and Cux2 are intrinsic and complementary regulators of dendrite branching, spine development, and synapse formation in layer II-III neurons of the cerebral cortex. Cux genes control the number and maturation of dendritic spines partly through direct regulation of the expression of Xlr3b and Xlr4b, chromatin remodeling genes previously implicated in cognitive defects. Accordingly, abnormal dendrites and synapses in Cux2(-/-) mice correlate with reduced synaptic function and defects in working memory. These demonstrate critical roles of Cux in dendritogenesis and highlight subclass-specific mechanisms of synapse regulation that contribute to the establishment of cognitive circuits., Depto. de Bioquímica y Biología Molecular, Fac. de Medicina, TRUE, pub

Heterozygous, pathogenic CUX1 variants are associated with global developmental delay or intellectual disability. This study delineates the clinical presentation in an extended cohort and investigates the molecular mechanism underlying the disorder in a Cux1+/− mouse model. Through international collaboration, we assembled the phenotypic and molecular information for 34 individuals (23 unpublished individuals). We analyze brain CUX1 expression and susceptibility to epilepsy in Cux1+/− mice. We describe 34 individuals, from which 30 were unrelated, with 26 different null and four missense variants. The leading symptoms were mild to moderate delayed speech and motor development and borderline to moderate intellectual disability. Additional symptoms were muscular hypotonia, seizures, joint laxity, and abnormalities of the forehead. In Cux1+/− mice, we found delayed growth, histologically normal brains, and increased susceptibility to seizures. In Cux1+/− brains, the expression of Cux1 transcripts was half of WT animals. Expression of CUX1 proteins was reduced, although in early postnatal animals significantly more than in adults. In summary, disease-causing CUX1 variants result in a non-syndromic phenotype of developmental delay and intellectual disability. In some individuals, this phenotype ameliorates with age, resulting in a clinical catch-up and normal IQ in adulthood. The post-transcriptional balance of CUX1 expression in the heterozygous brain at late developmental stages appears important for this favorable clinical course.

Heterozygous, pathogenic CUX1 variants are associated with global developmental delay or intellectual disability. This study delineates the clinical presentation in an extended cohort and investigates the molecular mechanism underlying the disorder in a Cux1+/− mouse model. Through international collaboration, we assembled the phenotypic and molecular information for 34 individuals (23 unpublished individuals). We analyze brain CUX1 expression and susceptibility to epilepsy in Cux1+/− mice. We describe 34 individuals, from which 30 were unrelated, with 26 different null and four missense variants. The leading symptoms were mild to moderate delayed speech and motor development and borderline to moderate intellectual disability. Additional symptoms were muscular hypotonia, seizures, joint laxity, and abnormalities of the forehead. In Cux1+/− mice, we found delayed growth, histologically normal brains, and increased susceptibility to seizures. In Cux1+/− brains, the expression of Cux1 transcripts was half of WT animals. Expression of CUX1 proteins was reduced, although in early postnatal animals significantly more than in adults. In summary, disease-causing CUX1 variants result in a non-syndromic phenotype of developmental delay and intellectual disability. In some individuals, this phenotype ameliorates with age, resulting in a clinical catch-up and normal IQ in adulthood. The post-transcriptional balance of CUX1 expression in the heterozygous brain at late developmental stages appears important for this favorable clinical course., Heterozygous, pathogenic CUX1 variants are associated with global developmental delay or intellectual disability. This study delineates the clinical presentation in an extended cohort and investigates the molecular mechanism underlying the disorder in a Cux1+/- mouse model. Through international collaboration, we assembled the phenotypic and molecular information for 34 individuals (23 unpublished individuals). We analyze brain CUX1 expression and susceptibility to epilepsy in Cux1+/- mice. We describe 34 individuals, from which 30 were unrelated, with 26 different null and four missense variants. The leading symptoms were mild to moderate delayed speech and motor development and borderline to moderate intellectual disability. Additional symptoms were muscular hypotonia, seizures, joint laxity, and abnormalities of the forehead. In Cux1+/- mice, we found delayed growth, histologically normal brains, and increased susceptibility to seizures. In Cux1+/- brains, the expression of Cux1 transcripts was half of WT animals. Expression of CUX1 proteins was reduced, although in early postnatal animals significantly more than in adults. In summary, disease-causing CUX1 variants result in a non-syndromic phenotype of developmental delay and intellectual disability. In some individuals, this phenotype ameliorates with age, resulting in a clinical catch-up and normal IQ in adulthood. The post-transcriptional balance of CUX1 expression in the heterozygous brain at late developmental stages appears important for this favorable clinical course.

Axons of the corpus callosum (CC) mediate the interhemispheric communication required for complex perception in mammals. In the somatosensory (SS) cortex, the CC exchanges inputs processed by the primary (S1) and secondary (S2) areas, which receive tactile and pain stimuli. During early postnatal life, a multistep process involving axonal navigation, growth, and refinement, leads to precise CC connectivity. This process is often affected in neurodevelopmental disorders such as autism and epilepsy. We herein show that in mice, expression of the axonal signaling receptor Neuropilin 1 (Nrp1) in SS layer (L) 2/3 is temporary and follows patterns that determine CC connectivity. At postnatal day 4, Nrp1 expression is absent in the SS cortex while abundant in the motor area, creating a sharp border. During the following 3 weeks, Nrp1 is transiently upregulated in subpopulations of SS L2/3 neurons, earlier and more abundantly in S2 than in S1. In vivo knock-down and overexpression experiments demonstrate that transient expression of Nrp1 does not affect the initial development of callosal projections in S1 but is required for subsequent S2 innervation. Moreover, knocking-down Nrp1 reduces the number of S2L2/3 callosal neurons due to excessive postnatal refinement. Thus, an exquisite temporal and spatial regulation of Nrp1 expression determines SS interhemispheric maps.