Growth and folding of the mammalian cerebral cortex: from molecules to malformations

Sun, Tao; Hevner, Robert F.

doi:10.1038/nrn3707

Cited by 437 publications

(428 citation statements)

References 207 publications

(265 reference statements)

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“…This overlap is consistent with coexpression of Lhx2 in Tbr2-positive (Eomes, T-box brain protein 2) basal progenitors at E15 (Fig. S4B), which generate these neurons (13). Conversely at P7, Lhx2 shows no overlapping staining with Ctip2-positive layer 5 neurons (chicken ovalbumin upstream promoter transcription factor-interacting protein 2) (Fig.…”

Section: Significancesupporting

confidence: 63%

“…3B) indicating that cortical progenitors have normal area identities in cKO embryos. Normal expression of TFs that are critical for cortical neurogenesis, such as Pax6 and Tbr2 (13,22), also indicates that the molecular specification and generation of the different cortical layer neurons does not require postmitotic activity of Lhx2. In fact, we analyzed this issue at P7 by using ISH for the specific cortical layer markers Cux2 (Cut-like homeobox 2, layer 2-3), RORb (layer 4), ER81 (layer 5), and Tbr1 (layer 6) and found that cortical layers appear indistinguishable among genotypes (Fig.…”

Section: Significancementioning

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: Significancesupporting

confidence: 63%

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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show abstract

“…This can be viewed as a forward or direct problem and is very straightforward to perform. Assuming a cortical thickness of 1.2 mm, 29 the result for the stack of Fig. 4 was 88.7 mL∕100 g tissue∕ min which is good agreement with values reported in the literature.…”

Section: Calculation Of Regional Blood Flowsupporting

confidence: 80%

Multimodal reconstruction of microvascular-flow distributions using combined two-photon microscopy and Doppler optical coherence tomography

et al. 2015

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Abstract. Computing microvascular cerebral blood flow (μCBF) in real cortical angiograms is challenging. Here, we investigated whether the use of Doppler optical coherence tomography (DOCT) flow measurements in individual vessel segments can help in reconstructing μCBF across the entire vasculature of a truncated cortical angiogram. A μCBF computational framework integrating DOCT measurements is presented. Simulations performed on a synthetic angiogram showed that the addition of DOCT measurements, especially close to large inflowing or outflowing vessels, reduces the impact of pressure boundary conditions and estimated vessel resistances resulting in a more accurate reconstruction of μCBF. Our technique was then applied to reconstruct microvascular flow distributions in the mouse cortex down to 660 μm by combining two-photon laser scanning microscopy angiography with DOCT.

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“…These data show BA17 has a thinner cortex compared to more anterior areas. This observation is most likely explained by natural rostro-caudal differences in cortical thickness, rather than ageing-induced neuron loss [28]. Discussion In this study, we have measured Aβ, phosphorylated tau (NFT), microglia, and astrocyte levels in five brain regions and have demonstrated both regional and individual variability in nine non-demented LBC1936 participants.…”

Section: Resultsmentioning

confidence: 98%

Assessing amyloid-β, tau, and glial features in Lothian Birth Cohort 1936 participants post-mortem

Tzioras¹,

Easter²,

Harris³

et al. 2017

Matters

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Growth and folding of the mammalian cerebral cortex: from molecules to malformations

Cited by 437 publications

References 207 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

Multimodal reconstruction of microvascular-flow distributions using combined two-photon microscopy and Doppler optical coherence tomography

Assessing amyloid-β, tau, and glial features in Lothian Birth Cohort 1936 participants post-mortem

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