Brain-Derived Neurotrophic Factor Promotes Implantation and Subsequent Placental Development by Stimulating Trophoblast Cell Growth and Survival

Abstract

Successful implantation of the blastocyst and subsequent placental development is essential for reproduction. Expression of brain-derived neurotrophic factor (BDNF) and neurotrophin-4/5, together with their receptor, tyrosine kinase B (TrkB), in trophectoderm cells of blastocyst suggests their potential roles in implantation and placental development. Here we demonstrated that treatment with BDNF promoted blastocyst outgrowth, but not adhesion, in vitro and increased levels of the cell invasion marker matrix metalloproteinase-9 in cultured blastocysts through the phosphatidylinositol 3-kinase pathway. After implantation, BDNF and neurotrophin-4/5 proteins as well as TrkB were expressed in trophoblast cells and placentas during different stages of pregnancy. Both TrkB and its ligands were also expressed in decidual cells. Treatment of cultured trophoblast cells with the TrkB ectodomain, or a Trk receptor inhibitor K252a, suppressed cell growth as reflected by decreased proliferation and increased apoptosis, whereas an inactive plasma membrane nonpermeable K252b was ineffective. Studies using the specific inhibitors also indicated the importance of the phosphatidylinositol 3-kinase/Akt pathway in mediating the action of TrkB ligands. In vivo studies in pregnant mice further demonstrated that treatment with K252a, but not K252b, suppressed placental development accompanied by increases in trophoblast cell apoptosis and decreases in placental labyrinth zone at midgestation. In vivo K252a treatment also decreased fetal weight at late gestational stages. Our findings suggested important autocrine/paracrine roles of the BDNF/TrkB signaling system during implantation, subsequent placental development, and fetal growth by increasing trophoblast cell growth and survival.

BDNF rs6265 methylation and genotype interact on risk for schizophrenia

“…5 In the present work we focus our analysis on another popular gene in behavioral genetics, highly important in neurodevelopment and in system-level neural phenotypes and sensitive to environmental factors, the gene coding for the Brain Derived Neurotrophic Factor (BDNF). BDNF is a highly regulated protein, a crucial factor for the development of the feto-placental unit 6 and of the brain, 7 as well as for neural plasticity, energy metabolism, learning, episodic and working memory (WM) [7][8][9][10][11][12] and cancer. 13 The effects of BDNF on synaptic plasticity and neuron survival strongly suggest a role for this factor in schizophrenia, a neurodevelopmental disorder whose risk is heritable and characterized by physiological prefrontal cortex (PFC) dysfunction during WM, [14][15][16] as well as reduced prefrontal levels of BDNF.…”

Brain-derived neurotrophic factor from follicular fluid is positively associated with rate of mature ooocytes collected and cleavage rate in intracytoplasmic sperm injection patients

“…Kawamura et al [16] found BDNF could promote blastocyst development by increasing total cell numbers in blastocysts and inhibiting trophectoderm cells apoptosis. In another study, they demonstrated that BDNF could improve fetal growth by increasing trophoblast cell growth and survival during implantation and subsequent placental development through a certain autocrine or paracrine mechanism of modulation [17].…”

Le BDNF

“…Par exemple, il semble impliqué dans la régulation de l'homéo-stasie glucidique, mais aussi dans les processus liés à l'angiogenèse [3]. La découverte de l'expression du système BDNF/TrkB dans le placenta [4] suggé-rait son implication dans le développe-ment placentaire et foetal, ce qui a, de fait, été démontré récemment.…”

“…Le récepteur TrkB est, quant à lui, exprimé dans le trophospongium mais aussi dans la zone labyrinthique qui constitue la principale zone d'échange vasculaire foeto-maternelle [4,5]. Une étude combinant des expérimentations menées in vitro et in vivo chez des souris vient de démontrer l'importance du BDNF dans le dévelop-pement placentaire et foetal.…”

“…Ainsi, le traitement de cellules trophoblastiques placentaires par un inhibiteur pharmacologique des récepteurs Trk (le k252a) ou encore par l'ectodomaine TrkB, diminue la prolifération des trophoblastes et augmente l'apoptose. Ces résultats ont été confirmés in vivo chez des souris gestantes et ont clairement démontré que l'inhibition du système BDNF/TrkB diminuait l'épaisseur de la zone labyrinthique placentaire, ce qui a pour conséquence de diminuer la croissance des foetus [4]. Chez le rat, dans des modèles de RCIU induit par une restriction calorique ou protéique maternelle, il a été montré que le retard de croissance foetale est associé à une diminution de l'expression du BDNF placentaire et à une augmentation de l'expression de son récepteur TrkB [5,6].…”