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The architectonic type principle conceptualizes structural connections between brain areas in terms of the relative architectonic differentiation of connected areas. It has previously been shown that spatio-temporal interactions between the time and place of neurogenesis could underlie multiple features of empirical mammalian connectomes, such as projection existence and the distribution of projection strengths. However, so far no mechanistic explanation for the emergence of typically observed laminar patterns of projection origins and terminations has been tested. Here, we expand an in silico model of the developing cortical sheet to explore which factors could potentially constrain the development of laminar projection patterns. We show that manipulations which rely solely on spatio-temporal interactions, namely the relative density of laminar compartments, a delay in the neurogenesis of infragranular layers relative to layer 1, and a delay in the neurogenesis of supragranular layers relative to infragranular layers, do not result in the striking correlation between supragranular contribution to projections and the relative differentiation of areas that is typically observed in the mammalian cortex. In contrast, we find that if we introduce systematic variation in cell-intrinsic properties, coupling them with architectonic differentiation, the resulting laminar projection patterns closely mirror the empirically observed patterns. We also find that the spatio-temporal interactions posited to occur during neurogenesis are necessary for the formation of the characteristic laminar patterns. Hence, our results indicate that the specification of the laminar patterns of projection origins may result from systematic variation in a number of cell-intrinsic properties, superimposed on the previously identified spatio-temporal interactions which are sufficient for the emergence of the architectonic type principle on the level of inter-areal connectivity in silico., Author summary The organization of structural connections in the brain is crucial for determining brain function. One feature of cortico-cortical connections is the distribution of their origins and terminations across cortical layers, which has been reported to exhibit a striking correlation with the architectonic differentiation of the connected cortical areas. How these laminar patterns emerge during development remains an open question. Here, we explored possible scenarios using systematic simulation experiments. We built on prior simulation experiments, in which we found that realistic patterns of connection existence may arise from spatio-temporal interactions in a homogeneous cortical sheet. We extended the previous in silico model of the developing cortical sheet by adding laminar compartments, to probe the development of laminar patterns of connection origins. We found that we could not easily generate characteristic laminar origin patterns by modifying the spatio-temporal growth trajectory of the homogeneous developing cortical sheet (i.e. changing when and where otherwise identical neurons were generated). However, when we added cellular heterogeneity, by modifying a property of axon growth across the simulated cortical sheet, the simulation was able to generate laminar patterns of connection origins that exhibited a positive correlation with the difference in architectonic differentiation between connected areas, similar to the relationship that can be observed in the mammalian cortex.

Occludin(OCLN) mutations cause human microcephaly and cortical malformation. A tight junction component thought absent in neuroepithelium after neural tube closure, OCLN isoform-specific expression extends into corticogenesis. Full-length and truncated isoforms localize to neuroprogenitor centrosomes, but full-length OCLN transiently localizes to plasma membranes while only truncated OCLN continues at centrosomes throughout neurogenesis. Mimicking human mutations, full-length OCLN depletion in mouse and in human CRISPR/Cas9-edited organoids produce early neuronal differentiation, reduced progenitor self-renewal and increased apoptosis. Human neural progenitors were more severely affected, especially outer radial glial cells, which mouse embryonic cortex lacks. Rodent and human mutant progenitors displayed reduced proliferation and prolonged M-phase. OCLN interacted with mitotic spindle regulators, NuMA and RAN, while full-length OCLN loss impaired spindle pole morphology, astral and mitotic microtubule integrity. Thus, early corticogenesis requires full-length OCLN to regulate centrosome organization and dynamics, revealing a novel role for this tight junction protein in early brain development.

We previously reported a mutation in the cholesterol biosynthesis gene, hydroxysteroid (17-beta) dehydrogenase 7 (Hsd17b7(rudolph)), that results in striking embryonic forebrain dysgenesis. Here we describe abnormal patterns of neuroprogenitor proliferation in the mutant forebrain, namely, a decrease in mitotic cells within the ventricular zone (VZ) and an increase through the remainder of the cortex by E11.5. Further evidence suggests mutant cells undergo abnormal interkinetic nuclear migration (IKNM). Furthermore, intermediate progenitors are increased at the expense of apical progenitors by E12.5, and post-mitotic neurons are expanded by E14.5. In vitro primary neuron culture further supports our model of accelerated cortical differentiation in the mutant. Combined administration of a statin and dietary cholesterol in utero achieved partial reversal of multiple developmental abnormalities in the Hsd17b7(rudolph) embryo, including the forebrain. These results suggest that abnormally increased levels of specific cholesterol precursors in the Hsd17b7(rudolph) embryo cause cortical dysgenesis by altering patterns of neurogenesis.

International audience; The timing of cortical neurogenesis has a major effect on the size and organization of the mature cortex. The deletion of the LIM-homeodomain transcription factor Lhx2 in cortical progenitors by Nestin-cre leads to a dramatically smaller cortex. Here we report that Lhx2 regulates the cortex size by maintaining the cortical progenitor proliferation and delaying the initiation of neurogenesis. The loss of Lhx2 in cortical progenitors results in precocious radial glia differentiation and a temporal shift of cortical neurogenesis. We further investigated the underlying mechanisms at play and demonstrated that in the absence of Lhx2, the Wnt/β-catenin pathway failed to maintain progenitor proliferation. We developed and applied a mathematical model that reveals how precocious neurogenesis affected cortical surface and thickness. Thus, we concluded that Lhx2 is required for β-catenin function in maintaining cortical progenitor proliferation and controls the timing of cortical neurogenesis.

Traumatic brain injury (TBI) is frequently characterized by neuronal, axonal and myelin loss, reactive gliosis and neuroinflammation, often associated with functional deficits. Endogenous repair mechanisms include production of new neurons from precursor cells, but usually the new neurons fail to integrate and survive more than a few weeks. This is in part mediated by the toxic and inflammatory environment present in the injured brain which activates precursor cells to proliferate and differentiate but limits survival of the newborn progeny. Therefore, an understanding of mechanisms that regulate production and survival of newborn neurons and the neuroinflammatory response after brain injury may lead to therapeutic options to improve outcomes. Suppressor of Cytokine Signaling 2 (SOCS2) promotes hippocampal neurogenesis and survival of newborn neurons in the adult brain and regulates anti-inflammatory responses in the periphery, suggesting it may be a useful candidate to improve outcomes of TBI. In this study the functional and cellular responses of SOCS2 over-expressing transgenic (SOCS2Tg) mice were compared to wildtype littermates following mild or moderately severe TBI. Unlike wildtype controls, SOCS2Tg mice showed functional improvement on a ladder test, with a smaller lesion volume at 7d post injury and increased numbers of proliferative CD11b+ microglia/macrophages at 35d post-injury in the mild injury paradigm. At 7d post-moderately severe injury there was an increase in the area covered by cells expressing an anti-inflammatory M2 phenotype marker (CD206+) but no difference in cells with a pro-inflammatory M1 phenotype marker (CD16/32+). No effect of SOCS2 overexpression was observed in production or survival of newborn neurons, even in the presence of the neuroprotective agent erythropoietin (EPO). Therefore, SOCS2 may improve outcome of TBI in mice by regulating aspects of the neuroinflammatory response, promoting a more anti-inflammatory environment, although this was not sufficient to enhance survival of newborn cortical neurons.

J. Neurochem. (2009) 112, 924–939. Abstract Fibroblast growth factor (FGF) mediated signaling is essential to many aspects of neural development. Activated FGF receptors signal primarily through the FGF receptor substrate (Frs) adapters, which include Frs2/Frs2α and Frs3/Frs2β. While some studies suggest that Frs3 can compensate for the loss of Frs2 in transfected cells, the lack of an effective Frs3 specific antibody has prevented efforts to determine the role(s) of the endogenous protein. To this end, we have generated a Frs3 specific antibody and have characterized the pattern of Frs3 expression in the developing nervous system, its subcellular localization as well as its biochemical properties. We demonstrate that Frs3 is expressed at low levels in the ventricular zone of developing cortex, between E12 and E15, and it co-localizes with nestin and acetylated α-tubulin in radial processes in the ventricular/subventricular zones as well as with βIII tubulin in differentiated cortical neurons. Subcellular fractionation studies demonstrate that endogenous Frs3 is both soluble and plasma membrane associated while Frs3 expressed in 293T cells associates exclusively with lipid rafts. Lastly, we demonstrate that neuronal Frs3 binds microtubules comparable to the microtubule-associated protein, MAP2, while Frs2 does not. Collectively, these data suggest that neuronal Frs3 functions as a novel microtubule binding protein and they provide the first biochemical evidence that neuronal Frs3 is functionally distinct from Frs2/Frs2α.