IGF system and foetal and postnatal growth

Irène Netchine
Team Leader : Irène Netchine
Administrative contact : Erwan Leforestier

Hopital Saint-Antoine - Bâtiment Kourilsky - 5ème étage - 184, rue du Faubourg Saint-Antoine, 75012 Paris, France

Research IGF system and foetal and postnatal growth

Epigenetic, genetic and environmental factors are involved in the regulation of growth. Any disturbance affecting one of these factors can lead to abnormal growth in either fetal and/or postnatal periods. Intra-uterine growth retardation (IUGR) is associated with severe morbidity and mortality, and especially an enhanced metabolic risk. On the other hand, overgrowth syndromes are associated to an enhanced risk of tumor during childhood. Fetal and/or early postnatal alterations lead to a differential growth trajectory and to an alteration of energetic metabolism. We demonstrated in mice that nutrition during lactation can stimulate growth and program the adult size through a different setting of the neuroendocrine somatotropic axis. This is associated with a different sensitivity to develop cardio-metabolic pathologies in adulthood. Our goals, detailed in four axes below, are to improve the early detection of abnormal fetal growth and tumors-risk, understand the regulation of growth and metabolism in order to propose and help in the design for new treatment strategies to improve growth, metabolic and tumoral prognosis.

  • To better understand the physiopathology of imprinting disorders (ID), we are increasing our cohorts of children born Small for Gestational age, or affected by Silver Russell Syndrome (SRS) and, in mirror, children born with over growth (Beckwith Wiedemann Syndrome).We aim to further decipher the molecular mechanisms of these imprinting disorders and to identify new molecular causes of SRS and BWS. For this purpose, we develop a high-throughput approach by next generation sequencing using an in house designed genes panel.
  • In the absence of appropriate mice models to explore Human imprinted disorders (ID) and because of the difficulty to collect tissues of interest from the patients, we aim to establish pluripotent stem cells (iPSCs) derived from SRS and BWS patients. These cellular models of IDs will be derived into specialized cells of interest (chondrocytes, adipose tissue, neurons) to document the consequences of IDs in these tissues.
  • Among imprinted genes, Delta-like homologue 1 (DLK1) is of special interest since its down-regulation leads to fetal growth restriction (FGR) and GH deficiency in some cases. We are deciphering the role of DLK1 in fetal and postnatal growth. We are notably testing if circulating DLK1 serum levels in the pregnant mothers can be used as a biomarker of FGR in humans. In parallel, in murine models, we are investigating the role of Dlk1 gene product into the regulation of linear growth during development.
  • With the purpose of measuring the impact of nutritional environment during the perinatal period on growth as well as cardio-metabolic diseases development, our project pursue the study of the mechanisms involved in the programming of growth and cardio-metabolic pathologies in mice when the perinatal nutrition is altered. In parallel, we take advantage of our large cohorts of patients with abnormal prenatal growth and imprinted disorders to study the long-term metabolic consequences of these conditions in Humans.

Highlights :

  1. We highlighted cellular mechanisms involved in the setting of growth target in response to the nutrition during the early postnatal period (lactation), and the particular role of nutritionally-regulated hormones like IGF1 (Decourtye et al, PLoS One. 2017 Jan 11;12(1):e0170083. doi: 10.1371/journal.pone.0170083).
  2. We have reported a large series of patients with imprinting defects on chromosome 14 (DLK1/GTL2 locus), usually affected in Temple Syndrome and showed that they have an important clinical overlap with patients with Silver Russell Syndrome, secondary to imprinting defects on chromosome 11 (IGF2/H19 locus), in keeping with an imprinting gene network. We aim to decipher the molecular mechanism(s) that are responsible for this clinical overlap (Geoffron et al, J Clin Endocrinol Metab. 2018 Jul 1;103(7):2436-2446. doi: 10.1210/jc.2017-02152).
  3. We have identified that genetic defects of the HMGA2-PLAG1-IGF2 pathway can lead to fetal and postnatal growth restriction, highlighting the role of this oncogenic pathway in the fine regulation of physiological fetal/postnatal growth. This work defines new genetic causes of Silver Russell Syndrome, important for genetic counseling (Abi Habib et al, Genet Med. 2018 Feb;20(2):250-258. doi: 10.1038/gim.2017.105).


Research Center
UMR_S 938

Hôpital St-Antoine


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