The cerebral cortex is the largest and most complex component of the mammalian brain, reaching its pinnacle in humans. The neocortex is the largest region of the cerebral cortex and is organized into "areas" that are functionally unique subdivisions distinguished by differences in cytoarchitecture, connectivity, and patterned gene expression. The specification of neocortical areas is controlled by an interplay between genetic regulation intrinsic to the neocortex, characterized by transcription factors (TFs) expressed by cortical progenitors, and extrinsic influences such as thalamocortical (TCA) input that relays sensory information to cortical areas. Proper area patterning of the cortex is a critical developmental event, because cortical areas form the basis for sensory perception, the control of our movements, and mediate our thoughts and behaviors. Although of undeniable importance, relatively little is known about the genetics of arealization. Current findings indicate a regulatory hierarchy that begins with patterning centers at the perimeter of the cerebral cortex that secrete morphogens, which in turn establish the graded expression of TFs in cortical progenitors that specify their area identities as well as those of their neuronal progeny. The major goal of this grant is to determine the TFs that control arealization, and define their roles in specifying area identities. The major issues to be addressed include: (1) defining the TFs that control the patterning of frontal / motor areas, and caudal / sensory (C/S) areas, as well as the interactions between these TFs to balance the rostral-caudal area patterning of the cortex, and (2) to distinguish roles for these TFs in the intrinsic genetic specification of area-specific properties in the cortical plate versus roles for TCA input in controlling the differentiation of area-specific properties and specializations that distinguish areas. Surprisingly, the size of each primary area in human neocortex varies by as much as two- to three-fold within the normal population. In mice, the sizes of a primary area can also vary significantly between individuals. These variations in area size can have dramatic effects on behavior. For example, genetic manipulations during embryonic development that result in proportional decreases or increases in the sizes primary areas in adults result in significant deficiencies at modality-specific behaviors. These findings indicate that areas have an optimal size, and underscore the importance of establishing during development the appropriate expression levels of TFs that specify area identities, as changes in them can result in a proportional change in area size, and thereby these early developmental events can have a prominent influence on behavior later in life, affecting performance and likely underlying many forms of cognitive dysfunction and neurological disorders. Therefore, the third major goal of this proposal is to establish the mouse as a model for relating differences in area patterning to variations in TF expression, and after validating this relationship, to use it as a basis to define roles for these TFs in area patterning in humans.

Public Health Relevance

The neocortex is the largest and most complex component of the mammalian brain, reaching a pinnacle in humans. This proposal addresses the genetic mechanisms that control the patterning of the neocortex intro areas-- anatomically and functionally distinct subdivisions responsible for sensory perception, voluntary movements, thinking and behaviors. The findings from the proposed aims will form a basis of understanding of cognitive dysfunction and neurological disorders.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Research Project (R01)
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Neurogenesis and Cell Fate Study Section (NCF)
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Panchision, David M
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Salk Institute for Biological Studies
La Jolla
United States
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Hatori, Megumi; Gill, Shubhroz; Mure, Ludovic S et al. (2014) Lhx1 maintains synchrony among circadian oscillator neurons of the SCN. Elife 3:e03357
Yau, Wai-Ying Wendy; Bischoff-Grethe, Amanda; Theilmann, Rebecca J et al. (2013) Alterations in white matter microstructure in women recovered from anorexia nervosa. Int J Eat Disord 46:701-8
Chou, Shen-Ju; Babot, Zoila; Leingartner, Axel et al. (2013) Geniculocortical input drives genetic distinctions between primary and higher-order visual areas. Science 340:1239-42
Chou, Shen-Ju; O'Leary, Dennis D M (2013) Role for Lhx2 in corticogenesis through regulation of progenitor differentiation. Mol Cell Neurosci 56:1-9
Zembrzycki, Andreas; Chou, Shen-Ju; Ashery-Padan, Ruth et al. (2013) Sensory cortex limits cortical maps and drives top-down plasticity in thalamocortical circuits. Nat Neurosci 16:1060-7
Kang, Ji-Yong; Kawaguchi, Daichi; Coin, Irene et al. (2013) In vivo expression of a light-activatable potassium channel using unnatural amino acids. Neuron 80:358-70
Li, Hao; Chou, Shen-Ju; Hamasaki, Tadashi et al. (2012) Neuregulin repellent signaling via ErbB4 restricts GABAergic interneurons to migratory paths from ganglionic eminence to cortical destinations. Neural Dev 7:10
Sahara, Setsuko; Yanagawa, Yuchio; O'Leary, Dennis D M et al. (2012) The fraction of cortical GABAergic neurons is constant from near the start of cortical neurogenesis to adulthood. J Neurosci 32:4755-61
Kawakami, Yasuhiko; Marti, Merce; Kawakami, Hiroko et al. (2011) Islet1-mediated activation of the *-catenin pathway is necessary for hindlimb initiation in mice. Development 138:4465-73
Hurtado de Mendoza, Tatiana; Perez-Garcia, Carlos G; Kroll, Todd T et al. (2011) Antiapoptotic protein Lifeguard is required for survival and maintenance of Purkinje and granular cells. Proc Natl Acad Sci U S A 108:17189-94

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