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Article Dans Une Revue PLoS Genetics Année : 2017

MITF – A controls branching morphogenesis and nephron endowment

Serge Garbay
  • Fonction : Auteur
Evelyne Fischer
  • Fonction : Auteur
Marco Pontoglio
  • Fonction : Auteur

Résumé

Congenital nephron number varies widely in the human population and individuals with low nephron number are at risk of developing hypertension and chronic kidney disease. The development of the kidney occurs via an orchestrated morphogenetic process where metanephric mesenchyme and ureteric bud reciprocally interact to induce nephron formation. The genetic networks that modulate the extent of this process and set the final nephron number are mostly unknown. Here, we identified a specific isoform of MITF (MITF-A), a bHLH-Zip transcription factor, as a novel regulator of the final nephron number. We showed that overexpression of MITF-A leads to a substantial increase of nephron number and bigger kidneys, whereas Mitfa deficiency results in reduced nephron number. Furthermore, we demonstrated that MITF-A triggers ureteric bud branching, a phenotype that is associated with increased ureteric bud cell proliferation. Molecular studies associated with an in silico analyses revealed that amongst the putative MITF-A targets, Ret was significantly modulated by MITF-A. Consistent with the key role of this network in kidney morphogenesis, Ret heterozygosis prevented the increase of nephron number in mice overexpressing MITF-A. Collectively, these results uncover a novel transcriptional network that controls branching morphogenesis during kidney development and identifies one of the first modifier genes of nephron endowment.
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Dates et versions

inserm-02159200 , version 1 (18-06-2019)

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Aurélie Phelep, Denise Laouari, Kapil Bharti, Martine Burtin, Salvina Tammaccaro, et al.. MITF – A controls branching morphogenesis and nephron endowment. PLoS Genetics, 2017, 13 (12), pp.e1007093. ⟨10.1371/journal.pgen.1007093⟩. ⟨inserm-02159200⟩
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