Lhx2 and Lhx9 Determine Neuronal Differentiation and Compartition in the Caudal Forebrain by Regulating Wnt Signaling

Karlsruhe Institute of Technology, Institute of Toxicology and Genetics, Karlsruhe, Germany.
PLoS Biology (Impact Factor: 11.77). 12/2011; 9(12):e1001218. DOI: 10.1371/journal.pbio.1001218
Source: PubMed

ABSTRACT Author Summary
The thalamus is the interface between the body and the brain. It connects sensory organs with higher brain areas and modulates processes such as sleep, alertness, and consciousness. Our knowledge about the embryonic development of this central relay station is still fragmented. Here, we show that the transcription factors Lhx2 and Lhx9 are essential for the development of the relay thalamus. Zebrafish embryos lacking Lhx2/Lhx9 have stalled neurogenesis - neuronal progenitor cells accumulate but do not complete their differentiation into thalamic neurons. In addition, we find that the neighboring Wnt-expressing epithalamus expands into the space containing mis-specified thalamus in these embryos. We identified a thalamus-specific cell adhesion modulator, Pcdh10b, which is controlled by canonical Wnt signaling. Altered Wnt-dependent Pcdh10b function in Lhx2/Lhx9-deficient embryos leads to intermingling of the thalamus and adjacent brain compartments and consequently regionalization within the caudal forebrain is lost. Organization of the developing CNS into molecularly distinct but transient segments and the implications for regional differentiation are well established for the developing hindbrain. We conclude that this applies to caudal forebrain too: Lhx2 and Lhx9 emerge as crucial factors driving neurogenesis and maintaining the regional integrity of the caudal forebrain. These are two prerequisites for the formation of this important relay station in the brain.


Available from: andrew lumsden, Jun 02, 2015
1 Follower
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Loss of neurons that express the neuropeptide hypocretin (Hcrt) has been implicated in narcolepsy, a debilitating disorder characterized by excessive daytime sleepiness and cataplexy. Cell replacement therapy, using Hcrt-expressing neurons generated in vitro, is a potentially useful therapeutic approach, but factors sufficient to specify Hcrt neurons are unknown. Using zebrafish as a high-throughput system to screen for factors that can specify Hcrt neurons in vivo, we identified the LIM homeobox transcription factor Lhx9 as necessary and sufficient to specify Hcrt neurons. We found that Lhx9 can directly induce hcrt expression and we identified two potential Lhx9 binding sites in the zebrafish hcrt promoter. Akin to its function in zebrafish, we found that Lhx9 is sufficient to specify Hcrt-expressing neurons in the developing mouse hypothalamus. Our results elucidate an evolutionarily conserved role for Lhx9 in Hcrt neuron specification that improves our understanding of Hcrt neuron development. © 2015. Published by The Company of Biologists Ltd.
    Development 02/2015; 142(6). DOI:10.1242/dev.117424 · 6.27 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Human embryonic stem cells (hESCs) may be applied to develop human-relevant sensitive in vitro test systems for monitoring developmental toxicants. The aim of this study was to identify potential developmental toxicity mechanisms of the histone deacetylase inhibitors (HDAC) valproic acid (VPA), suberoylanilide hydroxamic acid (SAHA) and trichostatin A (TSA) relevant to the in vivo condition using a hESC model in combination with specific differentiation protocols and genome-wide gene expression and microRNA profiling. Analysis of the gene expression data showed that VPA repressed neural tube and dorsal forebrain (OTX2, ISL1, EMX2 and SOX10)-related transcripts. In addition, VPA upregulates axonogenesis and ventral forebrain-associated genes, such as SLIT1, SEMA3A, DLX2/4 and GAD2. HDACi-induced expression of miR-378 and knockdown of miR-378 increases the expression of OTX2 and EMX2, which supports our hypothesis that HDACi targets forebrain markers through miR-378. In conclusion, multilineage differentiation in vitro test system is very sensitive for monitoring molecular activities relevant to in vivo neuronal developmental toxicity. Moreover, miR-378 seems to repress the expression of the OTX2 and EMX2 and therefore could be a regulator of the development of neural tube and dorsal forebrain neurons.
    Cell Death & Disease 05/2015; 6(5):e1756. DOI:10.1038/cddis.2015.121 · 5.18 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Despite its tremendous complexity the vertebrate nervous system emerges from a homogenous layer of neuroepithelial cells, the neural plate. Its formation relies on the time- and space-controlled progression of developmental programs. Apoptosis is a biological process that removes superfluous and potentially dangerous cells and is implemented through the activation of a molecular pathway conserved during evolution. Apoptosis and an unconventional function of one of its main effectors, caspase-3, contribute to the patterning and growth of the neuroepithelium. Little is known about the intrinsic and extrinsic cues controlling activities of the apoptotic machinery during development. The BarH-like (Barhl) proteins are homeodomain-containing transcription factors. Observations in C.elegans, Xenopus and mice document that Barhl proteins act in cell survival and as cell type-specific regulators of a caspase-3 function that limits neural progenitor proliferation. In this review we discuss the roles and regulatory modes of the apoptotic machinery in development of the neural plate. We focus on the Barhl2, the Sonic Hedgehog and the Wnt pathways and their activities in neural progenitors survival and proliferation. This article is protected by copyright. All rights reserved.
    genesis 01/2015; 53(2). DOI:10.1002/dvg.22844 · 2.04 Impact Factor