Downloaded from http://cshperspectives.cshlp.org/ on October 2, 2021 - Published by Cold Spring Harbor Laboratory Press Gradients in the Brain: The Control of the Development of Form and Function in the Cerebral Cortex Stephen N. Sansom and Frederick J. Livesey Gurdon Institute and Department of Biochemistry, University of Cambridge, Tennis Court Road, Cambridge, CB2 1QN Correspondence: [email protected] In the developing brain, gradients are commonly used to divide neurogenic regions into distinct functional domains. In this article, we discuss the functions of morphogen and gene expression gradients in the assembly of the nervous system in the context of the devel- opment of the cerebral cortex. The cerebral cortex is a mammal-specific region of the forebrain that functions at the top of the neural hierarchy to process and interpret sensory information, plan and organize tasks, and to control motor functions. The mature cerebral cortex is a modular structure, consisting of anatomically and functionally distinct areas. Those areas of neurons are generated from a uniform neuroepithelial sheet by two forms of gradients: graded extracellular signals and a set of transcription factor gradients operating across the field of neocortical stem cells. Fgf signaling from the rostral pole of the cerebral cortex sets up gradients of expression of transcription factors by both activating and repressing gene expression. However, in contrast to the spinal cord and the early Drosophila embryo, these gradients are not subsequently resolved into molecularly distinct domains of gene expression. Instead, graded information in stem cells is translated into dis- crete, region-specific gene expression in the postmitotic neuronal progeny of the stem cells. n the developing brain, gradients are com- the functions of morphogen and gene Imonly used to divide neurogenic regions expression gradients in the assembly of the into distinct functional domains. Examples of nervous system in the context of the develop- such gradients are the sonic hedgehog (Shh) ment of the cerebral cortex. The neocortex is gradient responsible for specifying dorsoventral the mammal-specific region of the forebrain fates in the spinal cord (Ericson et al. 1997), and that functions at the top of the neural hierarchy the double inverted gradients of the transcrip- to process and interpret sensory information, tion factors En1/2 and Pax2/5, induced by plan and organize tasks, and to control motor morphogens secreted from the isthmic organ- functions. A key aspect of the functional izer that pattern the midbrain and hindbrain anatomy of the cerebral cortex is that it is a (Sato et al. 2004). In this article, we discuss modular structure and, as is discussed, those Editors: James Briscoe, Peter Lawrence, and Jean-Paul Vincent Additional Perspectives on Generation and Interpretation of Morphogen Gradients available at www.cshperspectives.org Copyright # 2009 Cold Spring Harbor Laboratory Press; all rights reserved; doi: 10.1101/cshperspect.a002519 Cite this article as Cold Spring Harb Perspect Biol 2009;1:a002519 1 Downloaded from http://cshperspectives.cshlp.org/ on October 2, 2021 - Published by Cold Spring Harbor Laboratory Press S.N. Sansom and F.J. Livesey modules of neurons are generated from a neu- and gene expression. In the first accurate roepithelial sheet by two forms of gradients: histological analysis, Brodmann divided the graded extracellular signals and a set of tran- human neocortex into areas based on serial sec- scription factor gradients operating across the tioning to produce a map of cortical areas field of neocortical stem cells. (Brodmann 2006). Brodmann’s maps have been largely confirmed by subsequent investi- gations, including studies involving electro- THE NEOCORTEX: A SIX-LAYERED SHEET physical perturbation in live subjects and OF NEURONS DIVIDED INTO neurosurgical procedures on conscious patients FUNCTIONAL AREAS under local anesthesia (Mountcastle 1998). The In humans, the neocortex accounts for nearly functional importance of neocortical areas is three-quarters of the brain volume and also known from the examination of subjects contains more than twenty billion neurons that have suffered loss or damage to particular (Mountcastle 1998). The neocortex is com- areas—for example, damage to Broca’s or posed of six layers of neurons, and those layers Wernicke’s areas in the left hemisphere result differ markedly in neuronal cell type com- in an inability to process language and generate position, cell density, and connectivity. The speech. neurons of the neocortex are characteristically In all species, the neocortex contains three arrayed into vertical groups that span the corti- major areas along the rostrocaudal axis cal layers. In humans, neocortical columns are (Fig. 1B): the rostral motor cortex, the medial approximately 2 mm tall, have a diameter of somatosensory cortex, and the caudal visual 0.5 mm, and contain approximately 60,000 cortex; although the relative sizes of those neurons (Rakic 2008). Neurons within col- areas differs markedly in different species. umns are highly interconnected and share a Although the broad organization of neocortical common function. At a finer scale, neocortical areas shows remarkable similarity in different columns can be subdivided into mini or micro- mammals, the evolution of the neocortex is columns, which contain tens to hundreds of marked by a dramatic increase in cortical neurons, and have been proposed to comprise volume and in the total number of cortical the basic unit of the neocortex (Mountcastle areas. The neocortex of a mammal such as the 1998; Jones 2000; Rakic 2008). At the simplest shrew has a surface area a thousand-fold level of description, the deepest layers of cortical smaller than that of a human and has 10-fold neurons (layers 5 and 6) contain projection fewer functional areas (Striedter 2005). Under- neurons that connect areas of the cortex to standing the mechanisms that pattern the neo- one another or to subcortical structures. Layer cortex into the adult areas represents a major 4 is the layer within which most extracortical challenge and focus of modern developmental inputs arrive, particularly from the sensory neurobiology. thalamus, whereas the superficial layers are composed mainly of local circuits that form DEVELOPMENT OF THE NEOCORTEX— reciprocal connections with the deep layers THE RADIAL UNIT HYPOTHESIS (Fig. 1A) (Thomson and Lamy 2007). Groups of neocortical columns are orga- In mice, a model organism commonly used for nized into functionally distinct neocortical research in this area, development of the neo- areas, such that the cortex is a patchwork of cortex begins at embryonic day 9.5 (E9.5) with functional modules, including areas for motor the appearance of the cerebral vesicles from control, vision, and hearing (Fig. 1B). With the dorsal surface of the rostral neural tube. some notable exceptions, neocortical areas Initially, the neocortical primordium is com- lack obvious anatomical boundaries, being prised of an apparently homogenous pool distinguishable only by differences in cyto- of neural stem cells. The first postmitotic architecture, chemoarchitecture, connectivity, neurons of the neocortex, the Cajal-Retzius 2 Cite this article as Cold Spring Harb Perspect Biol 2009;1:a002519 Downloaded from http://cshperspectives.cshlp.org/ on October 2, 2021 - Published by Cold Spring Harbor Laboratory Press Gradients in the Brain AB 2/3 Olfactory bulb Rostral 4 Motor area lll Neocortical Motor area ll layers Motor area l 5 Precentral cortex, putative motor area Somatosensory area l 6 Somatosensory area ll Associative area Auditory area Retrospenial cortex Visual area ll Extracortical Visual area l Temporal cortex area ll Area 29d Caudal Figure 1. The arrangement of neocortical circuits and areas in the adult mouse brain. (A) The basic cortical circuit. Major extracortical inputs terminate in layer 4 and to a lesser degree in layer 6. Layer 4 neurons project to layers 2 and 3, which in turn innervate layers 5 and 6, the major output layers of the cortex. (B) Dorsal view of the adult mouse brain, with the functional roles of histologically defined areas labeled. Area maps redrawn from Wree et al. 1983. cells, appear at E10.5 to form a transient struc- visualize clones of neurons in the developing ture known as the marginal zone that later neocortex, failed to provide support for this becomes layer 1. The subsequent generation of model, instead finding evidence for both hori- the glutamatergic projection neurons of layers zontal and radial clones of cells (Price and 2–6 by neocortical stem cells takes place from Thurlow 1988; Walsh and Cepko 1992; Walsh E11 until approximately E17, with neurons of and Cepko 1993). However, after some debate, deep layers (layer 6) produced before those of subsequent studies of the subcortical origins the outer layers (2/3) (Fig. 2A). Postmitotic of inhibitory interneurons of the cortex and layer neurons born in the VZ migrate radially further lineage analyses confirmed the accuracy outwards to form the cortical layers that of the radial unit hypothesis (Tan and Breen together comprise the cortical plate. The out- 1993; Soriano et al. 1995; Anderson et al. wards migration of neurons of layers VI to II 1997). These studies revealed that the gluta- takes place along the processes of radial glial mergic neuronal progeny of neocortical stem cells that span the width of the developing neo- cells form radial columns that span the cortical cortex (Fig. 2B). Neurons of layer 6 are first to plate (Tan and Breen 1993; Soriano et al. leave the ventricular zone and migrate radially 1995) (Fig 2C). By contrast, the horizontal to form the nascent cortical plate. Neurons of clones observed in the initial retroviral studies layer V to II then migrate past those of layer were found to represent the tangential dis- VI and adopt successively superficial positions persion of inwardly migrating inhibitory (Fig. 2A). GABAergic interneurons arriving from the The radial migration of the neuronal ganglionic eminences of the ventral forebrain progeny of neocortical stem cells suggested (O’Rourke et al.