Showing papers by "Patrick Mehlen published in 2003"

Inhibition of Neuroepithelial Patched-Induced Apoptosis by Sonic Hedgehog

Abstract: During early development in vertebrates, Sonic hedgehog (Shh) is produced by the notochord and the floor plate. A ventrodorsal gradient of Shh directs ventrodorsal patterning of the neural tube. However, Shh is also required for the survival of neuroepithelial cells. We show that Patched (Ptc) induces apoptotic cell death unless its ligand Shh is present to block the signal. Moreover, the blockade of Ptc-induced cell death partly rescues the chick spinal cord defect provoked by Shh deprivation. Thus, the proapoptotic activity of unbound Ptc and the positive effect of Shh-bound Ptc on cell differentiation probably cooperate to achieve the appropriate spinal cord development.

The netrin-1 receptors UNC5H are putative tumor suppressors controlling cell death commitment.

Abstract: The three mammalian receptors UNC5H1, UNC5H2, and UNC5H3 (also named UNC5A, UNC5B, and UNC5C in human) that belong to the family of the netrin-1 receptors, UNC5H, were initially proposed as mediators of the chemorepulsive effect of netrin-1 on specific axons. However, they were also recently shown to act as dependence receptors. Such receptors induce apoptosis when unbound to their ligand. We show here that the expression of the human UNC5A, UNC5B, or UNC5C is down-regulated in multiple cancers including colorectal, breast, ovary, uterus, stomach, lung, or kidney cancers. In colorectal tumors, this down-regulation is associated with loss of heterozygosity occurring within UNC5A, UNC5B, and UNC5C genes but may also be partially related to epigenetic processes because histone deacetylase inhibitor increased UNC5C expression in various cancer cell lines. Moreover, sequencing of UNC5C gene in patients with colorectal tumors revealed the presence of missense mutations. The loss/reduction of expression may be a crucial mechanism for tumorigenicity because the expression of UNC5H1, UNC5H2, or UNC5H3 inhibits tumor cell anchorage-independent growth and invasion. Moreover, these hallmarks of malignant transformation can be restored by netrin-1 addition or apoptosis inhibition. Hence, UNC5H1, UNC5H2, and UNC5H3 receptors may represent tumor suppressors that inhibit tumor extension outside the region of netrin-1 availability by inducing apoptosis.

GDNF-deprived sympathetic neurons die via a novel nonmitochondrial pathway.

Abstract: The mitochondrial death pathway is triggered in cultured sympathetic neurons by deprivation of nerve growth factor (NGF), but the death mechanisms activated by deprivation of other neurotrophic factors are poorly studied. We compared sympathetic neurons deprived of NGF to those deprived of glial cell line–derived neurotrophic factor (GDNF). In contrast to NGF-deprived neurons, GDNF-deprived neurons did not die via the mitochondrial pathway. Indeed, cytochrome c was not released to the cytosol; Bax and caspase-9 and -3 were not involved; overexpressed Bcl-xL did not block the death; and the mitochondrial ultrastructure was not changed. Similarly to NGF-deprived neurons, the death induced by GDNF removal is associated with increased autophagy and requires multiple lineage kinases, c-Jun and caspase-2 and -7. Serine 73 of c-Jun was phosphorylated in both NGF- and GDNF-deprived neurons, whereas serine 63 was phosphorylated only in NGF-deprived neurons. In many NGF-deprived neurons, the ultrastructure of the mitochondria was changed. Thus, a novel nonmitochondrial caspase-dependent death pathway is activated in GDNF-deprived sympathetic neurons.

Meeting report: cellular dependence--old concept, new mechanisms.

Abstract: Programmed cell death occurs in response to both the presence of various extracellular factors and the lack of specific factors. Receptors that can mediate cell death in the absence of ligand binding are called dependence receptors, and they were the topic of the meeting held during the summer of 2003 in Fondation des Treilles, France. Not only is progress being made in the identification of new dependence receptors, but the partners that carry out this "negative" signal are also coming to light. With several of the receptors implicated in various human developmental disorders or disease states, gaining an understanding of the molecular mechanisms controlling dependence receptor-mediated cell death has clear clinical relevance.

Patched est un « récepteur à dépendance »

Abstract: > Il est classiquement admis qu’un recepteur ne devient actif qu’apres son interaction avec son ligand. Au cours des dernieres annees, cependant, un nouveau concept a peu a peu emerge suggerant que certains recepteurs dits « a dependance » peuvent delivrer deux messages: en presence de ligand, ces recepteurs transduisent un signal positif classique, stimulant par exemple une voie de differenciation; en l’absence de leur ligand en revanche, ils induisent la mort de la cellule par apoptose [1] (➜). Un article recemment paru dans la revue Science, emanant d’un travail collaboratif entre notre groupe et celui de N. Le Douarin, revele que le recepteur de Sonic Hedgehog (Shh), Patched (Ptc), fonctionne selon ce schema et que les deux actions de Ptc participent a la mise en place de la moelle epiniere [2]. L’activite pro-apoptotique de ces recepteurs en l’absence de leur ligand laisse supposer: (1) que ces recepteurs pourraient posseder une activite suppresseur de tumeur en eliminant les cellules tumorales qui se developperaient en dehors des zones d’expression normale du ligand ; (2) qu’un exces de mort cellulaire devrait survenir chez des animaux dont on aurait elimine experimentalement le ligand physiologique de ces recepteurs. Or, le recepteur Ptc repond a ces deux caracteristiques, ce qui explique notre interet pour cette proteine. Ptc est une proteine a douze domaines transmembranaires qui est le recepteur specifique de Shh, une molecule centrale lors du developpement, en particulier parce qu’elle induit le programme de determination-differenciation des neurones presents dans le tube neural, un tube s’etendant selon l’axe antero-posterieur des vertebres a l’origine de la moelle epiniere et du cerveau. Pourtant Ptc pourrait aussi etre un suppresseur de tumeur implique dans differents carcinomes. De plus, N. Le Douarin et al. avaient montre que, chez le poulet, le retrait experimental de Shh conduisait a une mort massive des neurones formant le tube neural [3]. Ce dernier resultat avait alors ete interprete par une communaute scientifique tres dogmatique, comme la consequence de l’absence d’un signal adequat de differenciation conduisant a la mort de ces cellules. Cependant, notre etude montre que le recepteur Ptc induit spontanement la mort des cellules tant que son ligand Shh n’est pas present. Cette induction d’apoptose semble passer par un clivage du dernier domaine intracellulaire de Ptc par les proteases centrales de l’apoptose que sont les caspases. Par ailleurs, grâce a l’utilisation d’une forme mutante de Ptc qui agit comme un dominant negatif de l’activite pro-apoptotique de Ptc, nous avons pu montrer que lors du developpement du poulet, on peut bloquer la mort des cellules du tube neural induite par le retrait experimental de Shh. De plus, l’action de ce dominant negatif ne se limite pas a bloquer la mort, mais conduit egalement a un developpement partiel du tube neural. Cette observation est conceptuellement alors tres interessante car elle suggere que la mort induite « experimentalement » par l’absence de Shh n’est pas la simple consequence d’une absence de differenciation mais revele en fait un mecanisme actif de modelage du tube neural par l’apoptose. On peut alors postuler que le developpement du tube neural controle par Shh passe a la fois par un mecanisme positif de determination-differenciation des neurones, mais aussi par l’inhibition d’un mecanisme negatif qui conduirait a la mort des neurones se developpant dans un contexte inapproprie. ◊ Patched is a dependence receptor NOUVELLE

Neurobiology: a new way to network.

Abstract: Guidance molecules called semaphorins ensure that nerve cells grow in the correct direction during development. It now appears that one semaphorin interacts with integrin proteins to produce another effect.