Prokineticin-1 (Prok-1) works coordinately with glial cell line-derived neurotrophic factor (GDNF) to mediate proliferation and differentiation of enteric neural crest cells.
Enteric neural crest cells (NCC) are multipotent progenitors which give rise to neurons and glia of the enteric nervous system (ENS) during fetal development. Glial cell line-derived neurotrophic factor (GDNF)/RET receptor tyrosine kinase (Ret) signaling is indispensable for their survival, migration and differentiation. Using microarray analysis and isolated NCCs, we found that 45 genes were differentially expressed after GDNF treatment (16 h), 29 of them were up-regulated including 8 previously undescribed genes. Prokineticin receptor 1 (PK-R1), a receptor for Prokineticins (Prok), was identified in our screen and shown to be consistently up-regulated by GDNF in enteric NCCs. Further, PK-R1 was persistently expressed at a lower level in the enteric ganglions of the c-Ret deficient mice when compared to that of the wild-type littermates. Subsequent functional analysis showed that GDNF potentiated the proliferative and differentiation effects of Prok-1 by up-regulating PK-R1 expression in enteric NCCs. In addition, expression analysis and gene knock-down experiments indicated that Prok-1 and GDNF signalings shared some common downstream targets. More importantly, Prok-1 could induce both proliferation and expression of differentiation markers of c-Ret deficient NCCs, suggesting that Prok-1 may also provide a complementary pathway to GDNF signaling. Taken together, these findings provide evidence that Prok-1 crosstalks with GDNF/Ret signaling and probably provides an additional layer of signaling refinement to maintain proliferation and differentiation of enteric NCCs.
Ngan
Elly S W
ES
Department of Surgery, University of Hong Kong, Pokfulam, Hong Kong. engan@hkucc.hku.hk
Shum
Cathy K Y
CK
Poon
Hiu-Ching
HC
Sham
Mai-Har
MH
Garcia-Barcelo
Maria-Mercè
MM
Lui
Vincent C H
VC
Tam
Paul K H
PK
D000818:Animals; D002454:Cell Differentiation / Q000235:genetics; D049109:Cell Proliferation; D004622:Embryo, Mammalian; D017615:Enteric Nervous System / Q000196:embryology*; D016326:Extracellular Matrix Proteins / Q000235:genetics; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D006023:Glycoproteins / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D008954:Models, Biological; D009432:Neural Crest / Q000378:metabolism / Q000502:physiology*; D020411:Oligonucleotide Array Sequence Analysis; D051096:Proto-Oncogene Proteins c-ret / Q000235:genetics; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism; D042662:Vascular Endothelial Growth Factor, Endocrine-Gland-Derived / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D014660:Vasoactive Intestinal Peptide / Q000235:genetics
D016326:Extracellular Matrix Proteins; C495040:Gdnf protein, mouse; D051100:Glial Cell Line-Derived Neurotrophic Factor; D006023:Glycoproteins; C525015:PKR1 protein, mouse; D043562:Receptors, G-Protein-Coupled; D042662:Vascular Endothelial Growth Factor, Endocrine-Gland-Derived; C081451:olfactomedin; D014660:Vasoactive Intestinal Peptide; D051096:Proto-Oncogene Proteins c-ret