Chapter 4 - Area Patterning of the Mammalian Cortex

This paper describes an evolutionary process likely involved in hierarchic transitions in biological evolution at many levels, from genetics to social organization. It is related to the evolutionary process described as contingent neutral evolution (CNE). It involves a sequence of stages initiated by the spontaneous appearance of functional redundancy. This redundancy can be the result of gene duplication, symbiosis, cell-cell interactions, environmental supports, etc. The availability of redundant sources of biological functionality relaxes purifying selection and allows degenerative changes to accumulate in one or more of the duplicates, potentially degrading or otherwise fractionating its function. This degeneration will be effectively neutral so long as another maintains functional integrity. Sexual recombination can potentially sample different combinations of these sub functional alternatives, with the result that favorable synergistic interactions between independently degenerate duplicates will have a non-negligible probability of being uncovered. The expression of such a synergistic combinatorial effect will result in the irreversible degradation of any remaining autonomous functionality, thereby initiating selection to prevent breakup of co-dependency. This becomes relevant to the evolution of hierarchic transitions when two or more organisms reciprocally duplicate functions that each other requires. If the resulting relaxation of selection reliably persists for an extended evolutionary period it will tend to produce complementary degenerative effects in each organism, leading to their irreversible codependency and purifying selection to avoid loss of integrity of their higher order functional unity. This provides a partial inversion of Darwinian logic that explains how the potential costs of the loss of organism autonomy can be mitigated, enabling the incremental transition to a synergistic higher order unit of evolution.

During the short period of brain development, nature is able to build the only system we know capable of producing cognition, language, creativity, and consciousness. The neocortex – the outermost layer of the mammalian cerebrum – appears to be the biological substrate of these abilities. Its development requires not only the precise placement and wiring of billions of cells, but also the implementation of mechanisms to ensure a viable cognition despite sometimes dramatic perturbations. Today, this remarkably complex organisation is thought to be genetically encoded, and further refined by activity-dependent processes. We propose that mechanical morphogenesis – the capacity of homogeneously growing elastic tissue to produce complex shapes – can also play an important role. Out of homogeneous growth, mechanical morphogenesis can induce the segregation of the neocortex into mechanical and geometric modules – the neocortical folds. Through the feedback of physical forces on developing tissue, these modules can influence the differentiation and wiring of the neocortex, having a causal role on neocortical development, and providing adaptable and robust units for its evolution.

The development of complex neocortical organisations is thought to result from the interaction of genetic and activity-dependent processes. We propose that a third type of process – mechanical morphogenesis – may also play an important role. We review theoretical and experimental results in physics showing how even homogeneous growth can produce a variety of forms, in particular neocortical folding. The mechanical instabilities that produce these forms induce heterogeneous patterns of stress at the scale of the organ. We review the evidence showing how these stresses can influence cell proliferation, migration and apoptosis, cell differentiation and shape, migration and axonal guidance, and could thus be able to influence regional neocortical identity and connectivity.

The forebrain is the seat of higher-order brain functions, and many human neuropsychiatric disorders are due to genetic defects affecting forebrain development, making it imperative to understand the underlying genetic circuitry. Recent progress now makes it possible to begin fully elucidating the genomic regulatory mechanisms that control forebrain gene expression. Herein, we discuss the current knowledge of how transcription factors drive gene expression programs through their interactions with cis-acting genomic elements, such as enhancers; how analyses of chromatin and DNA modifications provide insights into gene expression states; and how these approaches yield insights into the evolution of the human brain.

Brodmann has pioneered structural brain mapping. He considered functional and pathological criteria for defining cortical areas in addition to cytoarchitecture. Starting from this idea of structural-functional relationships at the level of cortical areas, we will argue that the cortical architecture is more heterogeneous than Brodmann’s map suggests. A triple-scale concept is proposed that includes repetitive modular-like structures and micro- and meso-maps. Criteria for defining a cortical area will be discussed, considering novel preparations, imaging and optical methods, 2D and 3D quantitative architectonics, as well as high-performance computing including analyses of big data. These new approaches contribute to an understanding of the brain on multiple levels and challenge the traditional, mosaic-like segregation of the cerebral cortex.

Elucidating the genetic control of cerebral cortical (pallial) development is essential for understanding function, evolution, and disorders of the brain. Transcription factors (TFs) that embryonically regulate pallial regionalization are expressed in gradients, raising the question of how discrete domains are generated. We provide evidence that small enhancer elements active in protodomains integrate broad transcriptional information. CreER^T2 and GFP expression from 14 different enhancer elements in stable transgenic mice allowed us to define a comprehensive regional fate map of the pallium. We explored transcriptional mechanisms that control the activity of the enhancers using informatics, in vivo occupancy by TFs that regulate cortical patterning (CoupTFI, Pax6, and Pbx1), and analysis of enhancer activity in Pax6 mutants. Overall, the results provide insights into how broadly expressed patterning TFs regulate the activity of small enhancer elements that drive gene expression in pallial protodomains that fate map to distinct cortical regions.