Neocortical arealization: Evolution, mechanisms, and open questions

Abstract

The mammalian neocortex is a structure with no equals in the vertebrates and is the seat of the highest cerebral functions, such as thoughts and consciousness. It is radially organized into six layers and tangentially subdivided into functional areas deputed to the elaboration of sensory information, association between different stimuli, and selection and triggering of voluntary movements. The process subdividing the neocortical field into several functional areas is called "arealization". Each area has its own cytoarchitecture, connectivity, and peculiar functions. In the last century, several neuroscientists have investigated areal structure and the mechanisms that have led during evolution to the rising of the neocortex and its organization. The extreme conservation in the positioning and wiring of neocortical areas among different mammalian families suggests a conserved genetic program orchestrating neocortical patterning. However, the impressive plasticity of the neocortex, which is able to rewire and reorganize areal structures and connectivity after impairments of sensory pathways, argues for a more complex scenario. Indeed, even if genetics and molecular biology helped in identifying several genes involved in the arealization process, the logic underlying the neocortical bauplan is still beyond our comprehension. In this review, we will introduce the present knowledge and hypotheses on the ontogenesis and evolution of neocortical areas. Then, we will focus our attention on some open issues, which are still unresolved, and discuss some recent studies that might open new directions to be explored in the next few years.

Postmitotic control of sensory area specification during neocortical development

“…This scenario is mainly based on mouse models in which several mitotically and postmitotically expressed genes were genetically manipulated, resulting ultimately in changes of the size and position of neocortical areas. As expected, alterations in expression levels of these patterning genes led to areal changes in accordance with their expression gradient 6,47 . However, the exact roles of mitotic and postmitotic gene gradients in the final specification of areal properties and how the primordial areal map is translated from progenitors to newborn neurons are still under debate.…”

“…However, areal commitment begins much earlier than laminar fate determination. The first rough regionalization of the neocortical field ('protomap') starts around E8.5 and relies mainly on the interplay between morphogens (FGFs, BMPs and WNTs) and transcription factors (Pax6, Emx2, COUP-TFI and Sp8), expressed in and around the cortical neuroepithelium [6][7][8][9] . Neocortical neurons are generated from E10.5, when neuroepithelial progenitors differentiate into radial glia cells (RGCs) that initiate neurogenesis 10 .…”

Corticostriatal connectivity and its role in disease

“…Recent work has pinpointed molecular mechanisms that establish layer 2/3→PT connections, showing that the synaptic connectivity depends on expression of the Shh-receptor Boc (Brother of CDO) in presynaptic layer 2/3 pyramidal neurons and sonic hedgehog (Shh) in postsynaptic PT neurons 188, 189 . How cell-type specification across layers relates to regional specification of cortical areas 190-192 remains unclear, but further efforts in this area may illuminate the basis both for inter-areal functional differences within classes of CStr projection neurons (e.g. 50, 193 ) and for the striking sub-regional specificity of many of the disorders involving CStr neurons discussed below.…”

Optix defines a neuroepithelial compartment in the optic lobe of the Drosophila brain

“…The formation of compartments ensures that cells in neighbouring rhombomeres segregate away from each other to maintain tissue boundaries. The embryonic neocortex is ‘arealized’, meaning that it is partitioned into regions with distinct functions, architectural organisation and gene expression signatures (reviewed in [14,15]). Each territory is subdivided by the action of signalling centres and transcription factor expression.…”