LKB1 signaling in cephalic neural crest cells is essential for vertebrate head development

Creuzet, Sophie; Viallet, Jean; Ghawitian, Maya; Torch, Sakina; Thélu, Jacques; Alrajeh, Moussab; Radu, Aurelian; Bouvard, Daniel; Costagliola, Floriane; Borgne, Maïlys Le; Buchet-Poyau, Karine; Aznar, Nicolas; Büschlen, Sylvie; Hosoya, Hiroshi; Thibert, Chantal; Billaud, Marc

doi:10.1016/j.ydbio.2016.08.006

Cited by 10 publications

(25 citation statements)

References 59 publications

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“…Collectively, this study and our previous report ( 18 ) identify the LKB1 pathway as a central orchestrator of neural crest development and highlight the pivotal role of energy metabolism in the formation of NCC lineages. These findings also raise the idea that a dysfunctional LKB1 signaling network could underlie the metabolic etiology of human neurocristopathies including peripheral neuropathies and intestinal motility disorders.…”

Section: Discussionsupporting

confidence: 74%

“…We recently showed that Lkb1 governs delamination, migration, differentiation, and survival of cephalic NCC, these complex morphogenetic processes being essential for vertebrate head formation ( 18 ). To further understand the contribution of Lkb1 to the establishment of neural crest lineages, we disrupted this gene in a subset of vagal and truncal mouse NCC using the tyrosinase Cre (Tyr::Cre) transgene.…”

Section: Introductionmentioning

confidence: 99%

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LKB1 specifies neural crest cell fates through pyruvate-alanine cycling

et al. 2019

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Metabolic processes underlying the development of the neural crest, an embryonic population of multipotent migratory cells, are poorly understood. Here, we report that conditional ablation of the Lkb1 tumor suppressor kinase in mouse neural crest stem cells led to intestinal pseudo-obstruction and hind limb paralysis. This phenotype originated from a postnatal degeneration of the enteric nervous ganglia and from a defective differentiation of Schwann cells. Metabolomic profiling revealed that pyruvate-alanine conversion is enhanced in the absence of Lkb1. Mechanistically, inhibition of alanine transaminases restored glial differentiation in an mTOR-dependent manner, while increased alanine level directly inhibited the glial commitment of neural crest cells. Treatment with the metabolic modulator AICAR suppressed mTOR signaling and prevented Schwann cell and enteric defects of Lkb1 mutant mice. These data uncover a link between pyruvate-alanine cycling and the specification of glial cell fate with potential implications in the understanding of the molecular pathogenesis of neural crest diseases.

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Section: Discussionsupporting

confidence: 74%

Section: Introductionmentioning

confidence: 99%

LKB1 specifies neural crest cell fates through pyruvate-alanine cycling

et al. 2019

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“…When activated, AMPK promotes energy-producing catabolic pathways while inhibiting anabolic pathways, such as cell growth and proliferation. Besides its role as an energy sensor, it also plays a role in cell differentiation and development of organisms [ 6 ]. In Caenorhabditis elegans , AMPKα promotes cell survival and arrests germline development during nutrient stress [ 7 ].…”

Section: Introductionmentioning

confidence: 99%

DictyosteliumAMPKα regulates aggregate size and cell-type patterning

Maurya¹,

Kumar²,

Saran³

2017

Open Biol.

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Starved Dictyostelium cells aggregate into groups of nearly 105 cells. AMPK is a highly conserved serine/threonine protein kinase consisting of a catalytic and two regulatory subunits. As multi-cellular development in Dictyostelium is initiated upon starvation, we explored the role of the energy sensor, AMPK, which shows significant similarity to human AMPK and is expressed throughout development. Deletion of the ampkα gene results in the formation of numerous small-sized aggregates that develop asynchronously to form few fruiting bodies with small sori and long stalks. On the other hand, ampkαOE cells form fruiting bodies with small stalks and large sori when compared with wild-type, Ax2. A minimum of 5% ampkα− cells in a chimaera with Ax2 cells was sufficient to reduce the aggregate size. Also, the conditioned media collected from ampkα− cells triggered Ax2 cells to form smaller aggregates. The starved ampkα− cells showed low glucose levels and formed large aggregates when glucose was supplied exogenously. Interestingly, ampkα− cells exhibit abnormal cell-type patterning with increased prestalk region and a concomitant reduction of prespore region. In addition, there was a loss of distinct prestalk/prespore boundary in the slugs.

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“…In cortical neurons, RanBP1 funtion in polarity is principaly mediated by the kinase LKB1 (Mencarelli et al, 2018). LKB1 is expressed and required in NC cells for their migration (Creuzet et al, 2016), raising the issue that the RanBP1-LKB1 pathway is at play during this process. To test this idea, we took advantage of a previously published Xenopus LKB1 kinase dead dominant negative construct (Ossipova et al, 2003).…”

Section: Lkb1 Mediates Ranbp1 Function During Neural Crest Cell Migra...mentioning

confidence: 99%

RanBP1 plays an essential role in directed migration of neural crest cells during development

Bariga

Alassadi

Mencarelli

et al. 2022

Preprint

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Collective cell migration is essential for embryonic development, tissue regeneration and repair, and has been implicated in pathological conditions such as cancer metastasis. It is, in part, directed by external cues that promote front-to-rear polarity in individual cells. However, our understanding of the pathways that underpin the directional movement of cells in response to external cues remains incomplete. To examine this issue we made use of neural crest cells (NC), which migrate as a collective during development to generate vital structures including bones and cartilage. Using a candidate approach, we found an essential role for Ran-binding protein 1 (RanBP1), a key effector of the nucleocytoplasmic transport pathway, in enabling directed migration of these cells. Our results indicate that RanBP1 is required for establishing front-to-rear polarity, so that NCs are able to chemotax. Moreover, our work suggests that RanBP1 function in chemotaxis involves the polarity kinase LKB1/PAR4. We envisage that regulated nuclear export of LKB1 through Ran/RanBP1 is a key regulatory step required for establishing front-to-rear polarity and thus chemotaxis, during NC collective migration.

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LKB1 signaling in cephalic neural crest cells is essential for vertebrate head development

Cited by 10 publications

References 59 publications

LKB1 specifies neural crest cell fates through pyruvate-alanine cycling

LKB1 specifies neural crest cell fates through pyruvate-alanine cycling

DictyosteliumAMPKα regulates aggregate size and cell-type patterning

RanBP1 plays an essential role in directed migration of neural crest cells during development

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