The bHLH transcription factor Hand2 is essential for the maintenance of noradrenergic properties in differentiated sympathetic neurons

Schmidt, Matthias; Lin, Shengyin; Pape, Manuela; Ernsberger, Uwe; Stanke, Matthias; Kobayashi, Kazuto; Howard, Marthe J.; Rohrer, Hermann

doi:10.1016/j.ydbio.2009.02.020

Cited by 58 publications

(68 citation statements)

References 35 publications

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“…6A). This finding, together with the previous demonstration that Hand2 controls proliferation of sympathoadrenergic precursors and immature neurons in vitro and in vivo (Hendershot et al, 2008;Reiff et al, 2010;Schmidt et al, 2009) and the presence of Hand2 expression in sympathetic ganglia (Fig. 6B), implicated Hand2 in the regulation of Alk expression.…”

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confidence: 82%

Midkine and Alk signaling in sympathetic neuron proliferation and neuroblastoma predisposition

et al. 2011

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SUMMARYNeuroblastoma (NB) is the most common extracranial solid tumor in childhood and arises from cells of the developing sympathoadrenergic lineage. Activating mutations in the gene encoding the ALK tyrosine kinase receptor predispose for NB. Here, we focus on the normal function of Alk signaling in the control of sympathetic neuron proliferation, as well as on the effects of mutant ALK. Forced expression of wild-type ALK and NB-related constitutively active ALK mutants in cultures of proliferating immature sympathetic neurons results in a strong proliferation increase, whereas Alk knockdown and pharmacological inhibition of Alk activity decrease proliferation. Alk activation upregulates NMyc and trkB and maintains Alk expression by an autoregulatory mechanism involving Hand2. The Alk-ligand Midkine (Mk) is expressed in immature sympathetic neurons and in vivo inhibition of Alk signaling by virus-mediated shRNA knockdown of Alk and Mk leads to strongly reduced sympathetic neuron proliferation. Taken together, these results demonstrate that the extent and timing of sympathetic neurogenesis is controlled by Mk/Alk signaling. The predisposition for NB caused by activating ALK mutations may thus be explained by aberrations of normal neurogenesis, i.e. elevated and sustained Alk signaling and increased NMyc expression. Activation of Alk signaling, in particular overexpression of ALK wt and NB ALK mutants resulted in the upregulation of NMyc and trkB, which may contribute to continued proliferation and NB predisposition. MATERIALS AND METHODS Expression plasmidsPcDNA3.1 expression plasmids for human ALK wt , ALK F1174L and ALK R1275Q, and pCAGGS expression plasmids for Hand2, Phox2b wt and Phox2b K155X have been described previously (Janoueix-Lerosey et al., 2008;Reiff et al., 2010). shRNA constructsThe shRNA against Gallus gallus Alk and Mk were designed using BLOCK-iT RNAi Designer (Invitrogen, Karlsruhe, Germany) and target the following sequences: shAlk, 5Ј-AAU GGU UUC UCU CUA UGU CCA ACU C-3Ј; shMk, 5Ј-GAG CUG ACU GCA AGU ACA AGU UUG A-3Ј. Scrambled shRNAs (sc-shRNA, Invitrogen, Karlsruhe, Germany) served as controls. In situ hybridizationNon-radioactive in situ hybridization on cryosections and preparation of digoxigenin labeled probes for chick Phox2b was carried out as described previously (Ernsberger et al., 1997;Stanke et al., 1999). qPCR analysisEqual amounts of RNA were used to synthesize cDNA with Oligo(dT)-primers and Superscript-III-reverse-transcriptase according to manufacturer's instructions (Invitrogen, Karlsruhe, Germany). The PCR was carried out using Abgene's Absolute Blue SYBR-Green qPCR Mix (Abgene, Epsom, UK) in a Stratagene Mx3000p Light Cycler (Stratagene, Waldbronn, Germany). All primers (MWG Biotech AG, Ebersberg, Germany) were designed to anneal optimally at 58°C with PerlPrimer (Marshall, 2004) (95°C for 30 seconds, 58°C for 30 seconds, 72°C for 30 seconds, repeated for 50 cycles and a subsequent dissociation curve). The primer pairs (see Table S1 in the supplementary material) were ...

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confidence: 82%

Midkine and Alk signaling in sympathetic neuron proliferation and neuroblastoma predisposition

et al. 2011

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“…Most other transcription factors that have been identified as regulators in the sympathoadrenal lineage primarily exert their effect on differentiation rather than proliferation. Early proliferative defects, similar to those found in Sox11-deficient as well as in Sox4 and Sox11 double-deficient SG, have been observed in mice deficient for Insm1 (Wildner et al, 2008), Hand2 (Hendershot et al, 2008;Schmidt et al, 2009) and Mash1 (Morikawa et al, 2009). In Sox4/Sox11-deficient and Insm1-deficient mice, proliferation rates were reduced until 12.5 dpc but had normalized or even increased above controls by 14.5 dpc.…”

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confidence: 66%

Sequential requirement of Sox4 and Sox11 during development of the sympathetic nervous system

et al. 2010

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SUMMARYThe highly related transcription factors Sox4 and Sox11 are expressed in the developing sympathetic nervous system. In the mouse, Sox11 appears first, whereas Sox4 is prevalent later. Using mouse mutagenesis and overexpression strategies in chicken, we studied the role of both SoxC proteins in this tissue. Neither Sox4 nor Sox11 predominantly functioned by promoting pan-neuronal or noradrenergic differentiation of sympathetic neurons as might have been expected from studies in neuronal precursors of the central nervous system. The transcriptional network that regulates the differentiation of sympathetic neurons remained intact and expression of noradrenergic markers showed only minor alterations. Instead, Sox11 was required in early sympathetic ganglia for proliferation of tyrosine hydroxylase-expressing cells, whereas Sox4 ensured the survival of these cells at later stages. In the absence of both Sox4 and Sox11, sympathetic ganglia remained hypoplastic throughout embryogenesis because of consecutive proliferation and survival defects. As a consequence, sympathetic ganglia were rudimentary in the adult and sympathetic innervation of target tissues was impaired leading to severe dysautonomia.

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“…A TF acting on terminal specification binds to cis-acting regulatory motifs present in target genes that determine the neurotransmitter phenotype and may continue later in life maintaining the same postmitotic identity (11). A similar scenario has been found more recently in vertebrates, after the identification of the genetic programs that give birth and maintain serotonergic (12), dopaminergic (13), and noradrenergic neurons (14) in the mouse nervous system. Less is known, however, about the specification of neuronal types expressing neuropeptide genes.…”

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Islet 1 specifies the identity of hypothalamic melanocortin neurons and is critical for normal food intake and adiposity in adulthood

Nasif

Souza

González

et al. 2015

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

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Food intake and body weight regulation depend on proper expression of the proopiomelanocortin gene (Pomc) in a group of neurons located in the mediobasal hypothalamus of all vertebrates. These neurons release POMC-encoded melanocortins, which are potent anorexigenic neuropeptides, and their absence from mice or humans leads to hyperphagia and severe obesity. Although the pathophysiology of hypothalamic POMC neurons is well understood, the genetic program that establishes the neuronal melanocortinergic phenotype and maintains a fully functional neuronal POMC phenotype throughout adulthood remains unknown. Here, we report that the early expression of the LIM-homeodomain transcription factor Islet 1 (ISL1) in the developing hypothalamus promotes the terminal differentiation of melanocortinergic neurons and is essential for hypothalamic Pomc expression since its initial onset and throughout the entire lifetime. We detected ISL1 in the prospective hypothalamus just before the onset of Pomc expression and, from then on, Pomc and Isl1 coexpress. ISL1 binds in vitro and in vivo to critical homeodomain binding DNA motifs present in the neuronal Pomc enhancers nPE1 and nPE2, and mutations of these sites completely disrupt the ability of these enhancers to drive reporter gene expression to hypothalamic POMC neurons in transgenic mice and zebrafish. ISL1 is necessary for hypothalamic Pomc expression during mouse and zebrafish embryogenesis. Furthermore, conditional Isl1 inactivation from POMC neurons impairs Pomc expression, leading to hyperphagia and obesity. Our results demonstrate that ISL1 specifies the identity of hypothalamic melanocortin neurons and is required for melanocortin-induced satiety and normal adiposity throughout the entire lifespan.hypothalamus | melanocortin | obesity | Isl1 | pomc

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The bHLH transcription factor Hand2 is essential for the maintenance of noradrenergic properties in differentiated sympathetic neurons

Cited by 58 publications

References 35 publications

Midkine and Alk signaling in sympathetic neuron proliferation and neuroblastoma predisposition

Midkine and Alk signaling in sympathetic neuron proliferation and neuroblastoma predisposition

Sequential requirement of Sox4 and Sox11 during development of the sympathetic nervous system

Islet 1 specifies the identity of hypothalamic melanocortin neurons and is critical for normal food intake and adiposity in adulthood

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