Sensory cortex limits cortical maps and drives top-down plasticity in thalamocortical circuits

Zembrzycki, Andreas; Chou, Shen-Ju; Ashery‐Padan, Ruth; Stoykova, Anastassia; O’Leary, Dennis D.M.

doi:10.1038/nn.3454

Cited by 69 publications

(54 citation statements)

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“…We examined Emx1Cre YL ;Pax6 cKO brains for evidence of cellular barrel walls and found that GAP43 expression does indeed display a barrellike expression pattern in an appropriate region of the Pax6 cKO cortex (Fig. 7 G and I), reduced in size as has been previously reported (21,22). Because both barrel walls and barrel cores form in the absence of Pax6, it is unlikely that Pax6 is a major target of Lhx2 with respect to the regulation of barrel formation.…”

Section: -H)mentioning

confidence: 52%

“…Upon cortex-specific loss of Pax6, a reduction in superficial layer neurons, similar to the defect in the Lhx2 cKO brain (17), is seen because of the premature exit of ventricular zone progenitors from the cell cycle (18). However, whisker-specific cytochrome oxidase-expressing barrel cores (21,22) as well as cellular barrel walls (this study) do form in the absence of Pax6. Therefore, a decrease in cortical neuronal number may not by itself explain the loss of barrel formation in the Lhx2 cKO.…”

Section: Emx1crementioning

confidence: 54%

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Lhx2 regulates a cortex-specific mechanism for barrel formation

Shetty

Godbole

Maheshwari

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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LIM homeodomain transcription factors are critical regulators of early development in multiple systems but have yet to be examined for a role in circuit formation. The LIM homeobox gene Lhx2 is expressed in cortical progenitors during development and also in the superficial layers of the neocortex in maturity. However, analysis of Lhx2 function at later stages of cortical development has been hampered by severe phenotypes associated with early loss of function. We identified a particular Cre-recombinase line that acts in the cortical primordium after its specification is complete, permitting an analysis of Lhx2 function in neocortical lamination, regionalization, and circuit formation by selective elimination of Lhx2 in the dorsal telencephalon. We report a profound disruption of cortical neuroanatomical and molecular features upon loss of Lhx2 in the cortex from embryonic day 11.5. A unique feature of cortical circuitry, the somatosensory barrels, is undetectable, and molecular patterning of cortical regions appears disrupted. Surprisingly, thalamocortical afferents innervate the mutant cortex with apparently normal regional specificity. Electrophysiological recordings reveal a loss of responses evoked by stimulation of individual whiskers, but responses to simultaneous stimulation of multiple whiskers were present, suggesting that thalamic afferents are unable to organize the neurocircuitry for barrel formation because of a cortex-specific requirement of Lhx2. We report that Lhx2 is required for the expression of transcription factor paired box gene 6, axon guidance molecule Ephrin A5, and the receptor NMDA receptor 1. These genes may mediate Lhx2 function in the formation of specialized neurocircuitry necessary for neocortical function.

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Section: -H)mentioning

confidence: 52%

Section: Emx1crementioning

confidence: 54%

Lhx2 regulates a cortex-specific mechanism for barrel formation

Shetty

Godbole

Maheshwari

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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“…This disordered pattern is propagated through afferent pathways to SI, where a jumbled representation of the hand replaces the normal somatotopic arrangement [101]. However, if the median nerve is severed very early in development, a considerable degree of somatotopy is retained in SI [102], suggesting that early in development, an existing cortical body map can direct the reorganization of thalamocortical projections following a disruption in the orderly patterning at the periphery [103]. …”

Section: Figurementioning

confidence: 99%

Body maps in the infant brain

Marshall

Meltzoff

2015

Trends in Cognitive Sciences

112

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Researchers have examined representations of the body in the adult brain, but relatively little attention has been paid to ontogenetic aspects of neural body maps in human infants. Novel applications of methods for recording brain activity in infants are delineating cortical body maps in the first months of life. Body maps may facilitate infants’ registration of similarities between self and other—an ability that is foundational to developing social cognition. Alterations in interpersonal aspects of body representations might also contribute to social deficits in certain neurodevelopmental disorders.

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“…This analysis shows that deletion of Lhx2 in postmitotic neurons broadly alters neuronal properties that affect area patterning across layers in the CP. (14,17,18), CoupTF1 (chicken ovalbumin upstream promoter transcription factor) (1,19), and Sp8 (specificity protein 8) immunolabelings (20,21) on E12 sagittal sections. The expression of TFs remained unchanged in the VZ in cKO sections (Fig.…”

Section: Significancementioning

confidence: 99%

Postmitotic regulation of sensory area patterning in the mammalian neocortex by Lhx2

Zembrzycki

Pérez-García

Wang

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Current knowledge suggests that cortical sensory area identity is controlled by transcription factors (TFs) that specify area features in progenitor cells and subsequently their progeny in a one-step process. However, how neurons acquire and maintain these features is unclear. We have used conditional inactivation restricted to postmitotic cortical neurons in mice to investigate the role of the TF LIM homeobox 2 (Lhx2) in this process and report that in conditional mutant cortices area patterning is normal in progenitors but strongly affected in cortical plate (CP) neurons. We show that Lhx2 controls neocortical area patterning by regulating downstream genetic and epigenetic regulators that drive the acquisition of molecular properties in CP neurons. Our results question a strict hierarchy in which progenitors dominate area identity, suggesting a novel and more comprehensive two-step model of area patterning: In progenitors, patterning TFs prespecify sensory area blueprints. Sequentially, sustained function of alignment TFs, including Lhx2, is essential to maintain and to translate the blueprints into functional sensory area properties in cortical neurons postmitotically. Our results reemphasize critical roles for Lhx2 that acts as one of the terminal selector genes in controlling principal properties of neurons.terminal selector genes | epigenetic mechanisms | neuronal fate | MeCP2 | CoupTF1T he adult mammalian cortex is patterned into distinct and modality-specific sensory areas that are responsible for the perception of the sensory information and for the control of behavior (1). Research has focused in particular on how transcription factors (TFs), which are expressed in gradients in the cortical ventricular zone (VZ) progenitors, drive area patterning of mature cortical sensory areas by specifying their size and position during early cortical development (1, 2). As a result, current views suggest that the specification of sensory area identity is dominated by patterning events in progenitors (1-3). However, the mechanisms that translate area-patterning information from cortical progenitors into area-specific properties of postmitotic (CP) neurons are not well understood. ResultsWe hypothesized that sensory area identity in CP neurons in mice could be determined ultimately by the function of key regulators that function postmitotically. One of the few TFs that are expressed in progenitors and neurons is LIM-homeodomain 2 (Lhx2) (4). During early corticogenesis, Lhx2 shows a caudal/ medial-high to rostral/lateral-low expression gradient in cortical progenitors. Starting from around embryonic day (E) 12 to postnatal day (P) 0, a caudal/lateral-high to rostral/medial-low expression gradient is apparent in cortical neurons (Fig. S1), which postnatally becomes restricted to more uniform expression in upper cortical layers (Fig. S1). Such sustained and dynamic expression of Lhx2 in neurons suggests that Lhx2, similarly to its established roles exerted in progenitors (4-8), may affect properties in cortical neurons...

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Sensory cortex limits cortical maps and drives top-down plasticity in thalamocortical circuits

Cited by 69 publications

References 50 publications

Lhx2 regulates a cortex-specific mechanism for barrel formation

Lhx2 regulates a cortex-specific mechanism for barrel formation

Body maps in the infant brain

Postmitotic regulation of sensory area patterning in the mammalian neocortex by Lhx2

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