Team 5 – STEM CELLS, SIGNALING AND PRIONS

Our research arises from a stem cell background to tackle basic and clinical challenges relating to neurodegeneration/neurotoxicity, bone/tooth mineralization and dental repair. Our team exploits stem cell lines to identify mechanisms sustaining the acquisition, the maintenance and the coordination of specialized functions. We notably study the regulation of key actors of cell homeostasis (transporters, receptors, microRNAs, signaling effectors) whose deregulation leads to pathological situations and are thereby potent therapeutic targets.

Using a neuroectodermal stem cell endowed with the capacity to differentiate into serotonergic or noradrenergic neurons (“Neuro-prion axis”), we discovered that a microRNA, mir16, relays the action of antidepressants such as Prozac. Mir16 is a central player in the adaptive response of neurons to antidepressants. This work provided the prime evidence that a pharmacological agent exerts its action by regulating a microRNA. This cell line was also instrumental to assign a signaling function to cellular prion protein PrPC that supports PrPC roles in neuronal differentiation and homeostasis. We further demonstrated that prion and Alzheimer’s diseases share common neurodegenerative mechanisms which are connected to the corruption of PrPC signaling, the overactivation of the ROCK and PDK1 kinases and the abrogation of TACE a-secretase protective activity. Our work posits the ROCK-PDK1 module as a therapeutic option to combat both prion and Alzheimer’s diseases as the inhibition of the ROCK/PDK1 kinases rescues TACE activity and mitigates these two pathologies in mice.

Our team also established mesoblastic stem cell lines able to recapitulate in vitro all the steps of osteogenesis, chondrogenesis and ondotogenesis programs (“Mineralized tissues axis”). We identified a serotonergic receptor involved in bone mineralization, whose deregulation in soft tissues leads to ectopic mineralization. We provided evidence that pulpal stem cells display a dual serotonergic/dopaminergic identity. This discovery permitted us to show that platelets, activated upon tooth injury, recruit pulpal stem cells for tooth repair.

Our current aims are to define:

  • how antidepressants modulate the expression of mir16 and mobilize the plasticity of neurons
  • PrPC roles in neuronal stem cells and neurons
  • how PDK1 is overactivated in prion and Alzheimer’s diseases and impacts on TACE protective activity
  • whether deregulation of the PrPC/ROCK-PDK1/TACE axis also contributes to neurodegeneration in other aggregate prone protein-based neurodegenerative diseases such as Parkinson’s disease, Amyotrophic Lateral Sclerosis, or SpinoCerebellar Ataxia.
  • how serotonergic and dopaminergic signaling contributes to the homeostasis of pulpal stem cells and their recruitment for tooth repair.

Key Words:

Stem cells, neuronal cell differentiation, mineralization processes, signaling, microRNA, prion biology, neurodegenerative diseases, therapeutic strategies.

 

Team leaders

Members

 

Significant recent publications

Deletion of serotonin 2B receptor provokes structural alterations of mouse dental tissues. 
Dimitrova-Nakov S
, Baudry A, Harichane Y, Collet C, Marchadier A, Kellermann O, Goldberg M : Calcif Tissue Int. 2014

A PrP(C)-caveolin-Lyn complex negatively controls neuronal GSK3β and serotonin 1B receptor. Hernandez-Rapp J, Martin-Lannerée S, Hirsch TZ, Pradines E, Alleaume-Butaux A, Schneider B, Baudry A, Launay JM, Mouillet-Richard S : Sci Rep, 2014

Essential Roles of Dopamine and Serotonin in Tooth Repair: Functional Interplay Between Odontogenic Stem Cells and Platelets. 
Baudry A
, Alleaume-Butaux A, Dimitrova-Nakov S, Goldberg M, Schneider B, Launay JM, Kellermann O : Stem Cells, 2015

Double-Edge Sword of Sustained ROCK Activation in Prion Diseases through Neuritogenesis Defects and Prion Accumulation. 
Alleaume-Butaux A
, Nicot S, Pietri M, Baudry A, Dakowski C, Tixador P, Ardila-Osorio H, Haeberlé AM, Bailly Y, Peyrin JM, Launay JM, Kellermann O, Schneider B : PLoS Pathog, 2015

Prion Protein Deficiency Causes Diverse Proteome Shifts in Cell Models That Escape Detection in Brain Tissue.
Mehrabian M, Brethour D, Williams D, Wang H, Arnould H, Schneider B, Schmitt-Ulms G : PLoSOne. 2016

PDK1 decreases TACE-mediated α-secretase activity and promotes disease progression in prion and Alzheimer’s diseases. 
Pietri M
, Dakowski C, Hannaoui S, Alleaume-Butaux A, Hernandez-Rapp J, Ragagnin A, Mouillet- Richard S, Haik S, Bailly Y, Peyrin JM, Launay JM, Kellermann O, Schneider B : Nat Med. 2013

Neuritogenesis: the prion protein controls β1 integrin signaling activity. 
Loubet D
, Dakowski C, Pietri M, Pradines E, Bernard S, Callebert J, Ardila-Osorio H, Mouillet- Richard S, Launay JM, Kellermann O, Schneider B : FASEB J. 2012

Concomitant multipotent and unipotent dental pulp progenitors and their respective contribution to mineralised tissue formation. 
Lacerda-Pinheiro S
, Dimitrova-Nakov S, Harichane Y, Souyri M, Petit-Cocault L, Legrès L,  Marchadier A, Baudry A, Ribes S, Goldberg M, Kellermann O, Poliard A : Eur Cell Mater. 2012

Raphe-mediated signals control the hippocampal response to SRI antidepressants via miR-16.
Launay JM, Mouillet-Richard S, Baudry A, Pietri M, Kellermann O : Transl Psychiatry. 2011

miR-16 targets the serotonin transporter: a new facet for adaptive responses to antidepressants. 
Baudry A
, Mouillet-Richard S, Schneider B, Launay JM, Kellermann O : Science. 2010

Recent Publications

Articles