Lhx2 regulates a cortex-specific mechanism for barrel formation

Shetty, Ashwin S.; Godbole, Geeta; Maheshwari, Upasana; Padmanabhan, Hari; Chaudhary, Rahul; Muralidharan, Bhavana; Hou, Pei Shan; Monuki, Edwin S.; Kuo, Hung‐Chi; Rema, V.; Tole, Shubha

doi:10.1073/pnas.1311158110

Cited by 56 publications

(68 citation statements)

References 56 publications

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“…S2). Contrary to deletion of Lhx2 in progenitors (4)(5)(6)(7)(8), our data demonstrate that gross cortical development is not affected by postmitotic deletion of Lhx2. This result allowed us to investigate processes that mature postnatally such as area patterning.…”

Section: Resultscontrasting

confidence: 89%

“…S1). Such sustained and dynamic expression of Lhx2 in neurons suggests that Lhx2, similarly to its established roles exerted in progenitors (4)(5)(6)(7)(8), may affect properties in cortical neurons. To test this hypothesis, we used conditional inactivation by crossing mice carrying floxed Lhx2 alleles (4) with mice expressing Nex-Cre mediating Cre recombination restricted to postmitotic cortical neurons (9) starting around E11 (Fig.…”

Section: Resultsmentioning

confidence: 99%

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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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Section: Resultscontrasting

confidence: 89%

Section: Resultsmentioning

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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“…Pax6 is likely to be one of such genes, as it is a key regulator for cortical progenitor proliferation and neurogenesis (33). Further, in cortical progenitors, the β-Cat/TCF complex was shown to activate Pax6 transcription by binding to the Pax6 promoter (34), and Lhx2 was also reported to directly regulate Pax6 expression by binding to its enhancers (35,36). We first confirmed that Pax6 is down-regulated in the cKO dTel at E12.5 (Fig.…”

Section: Wnt/β-cat Signaling Fails To Maintain Cortical Progenitor Inmentioning

confidence: 52%

Lhx2 regulates the timing of β-catenin-dependent cortical neurogenesis

Hsu

Nam

Cui

et al. 2015

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

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The timing of cortical neurogenesis has a major effect on the size and organization of the mature cortex. The deletion of the LIMhomeodomain transcription factor Lhx2 in cortical progenitors by Nestin-cre leads to a dramatically smaller cortex. Here we report that Lhx2 regulates the cortex size by maintaining the cortical progenitor proliferation and delaying the initiation of neurogenesis. The loss of Lhx2 in cortical progenitors results in precocious radial glia differentiation and a temporal shift of cortical neurogenesis. We further investigated the underlying mechanisms at play and demonstrated that in the absence of Lhx2, the Wnt/β-catenin pathway failed to maintain progenitor proliferation. We developed and applied a mathematical model that reveals how precocious neurogenesis affected cortical surface and thickness. Thus, we concluded that Lhx2 is required for β-catenin function in maintaining cortical progenitor proliferation and controls the timing of cortical neurogenesis.cortical neurogenesis | Lhx2 | β-catenin U nderstanding how genetic mechanisms interact to set up a precise developmental timing is a fundamental issue in biology. In the cerebral cortex, excitatory neurons are generated by progenitor cells in the dorsal telencephalon (dTel) lining the lateral ventricle. During the early developmental stages, cortical progenitors undergo symmetric divisions, resulting in the proliferation of progenitors and thereby allowing expansion of the developing cortex. Soon after, cortical progenitors start generating distinct types of neurons through asymmetric differentiative divisions (1-5). The precise timing of the switch from proliferative division to differentiative division is crucial to determining the number of cortical neurons, and thus the cortical size.The switch from proliferation to differentiation is reportedly regulated by the canonical Wnt signaling pathway, in which β-catenin (β-Cat) is the major downstream effector. In the absence of Wnt signaling, β-Cat is phosphorylated by glycogen synthase kinase 3 and targeted for proteosome degradation. Once Wnt ligands bind to the Frizzled-Lrp5/6 receptors, the activity of glycogen synthase kinase 3-Axin-APC (adenomatous polyposis coli) destruction complex is inhibited. As a consequence, β-Cat accumulates in the cytoplasm, translocates to the nucleus, and activates downstream gene transcription together with the lymphoid enhancer-binding factor (LEF)/ T-cell factor (TCF) transcription factors (6). Overexpression of the stabilized, N-terminally truncated form of β-Cat in cortical progenitors during early neurogenesis promotes their overproliferation (7,8), whereas inactivation of β-Cat in the cortex promotes neurogenesis (9, 10). However, stabilized β-Cat was also shown to promote cortical progenitor differentiation (11). Thus, it has been proposed that Wnt/β-Cat signaling promotes proliferation and differentiation of cortical progenitors at early and late developmental stages, respectively (12). This raises the essential and largely open question of ho...

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“…The cortical selector gene Lhx2 (Mangale et al, 2008) has additional functions in cortical development, including regulating precise thalamic innervation of sensory neocortex (Chou and O' Leary, 2013;Chou et al, 2009;Marcos-Mondejar et al, 2012;Roy et al, 2013;Shetty et al, 2013;Subramanian et al, 2011). Lhx2, like Emx2, Dmrt3 and Dmrta2, is expressed in a caudomedial high to rostrolateral low gradient.…”

Section: Patterning Interactions Among Dmrt Genes Emx2 and Wntsmentioning

confidence: 99%

The cortical hem regulates the size and patterning of neocortex

et al. 2014

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The cortical hem, a source of Wingless-related (WNT) and bone morphogenetic protein (BMP) signaling in the dorsomedial telencephalon, is the embryonic organizer for the hippocampus. Whether the hem is a major regulator of cortical patterning outside the hippocampus has not been investigated. We examined regional organization across the entire cerebral cortex in mice genetically engineered to lack the hem. Indicating that the hem regulates dorsoventral patterning in the cortical hemisphere, the neocortex, particularly dorsomedial neocortex, was reduced in size in latestage hem-ablated embryos, whereas cortex ventrolateral to the neocortex expanded dorsally. Unexpectedly, hem ablation also perturbed regional patterning along the rostrocaudal axis of neocortex. Rostral neocortical domains identified by characteristic gene expression were expanded, and caudal domains diminished. A similar shift occurs when fibroblast growth factor (FGF) 8 is increased at the rostral telencephalic organizer, yet the FGF8 source was unchanged in hem-ablated brains. Rather we found that hem WNT or BMP signals, or both, have opposite effects to those of FGF8 in regulating transcription factors that control the size and position of neocortical areas. When the hem is ablated a necessary balance is perturbed, and cerebral cortex is rostralized. Our findings reveal a much broader role for the hem in cortical development than previously recognized, and emphasize that two major signaling centers interact antagonistically to pattern cerebral cortex.

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Lhx2 regulates a cortex-specific mechanism for barrel formation

Cited by 56 publications

References 56 publications

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

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

Lhx2 regulates the timing of β-catenin-dependent cortical neurogenesis

The cortical hem regulates the size and patterning of neocortex

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