FGF15 promotes neurogenesis and opposes FGF8 function during neocortical development.
BACKGROUND
Growth, differentiation and regional specification of telencephalic domains, such as the cerebral cortex, are regulated by the interplay of secreted proteins produced by patterning centers and signal transduction systems deployed in the surrounding neuroepithelium. Among other signaling molecules, members of the fibroblast growth factor (FGF) family have a prominent role in regulating growth, differentiation and regional specification. In the mouse telencephalon the rostral patterning center expresses members of the Fgf family (Fgf8, Fgf15, Fgf17, Fgf18). FGF8 and FGF17 signaling have major roles in specification and morphogenesis of the rostroventral telencephalon, whereas the functions of FGF15 and FGF18 in the rostral patterning center have not been established.


RESULTS
Using Fgf15-/- mutant mice, we provide evidence that FGF15 suppresses proliferation, and that it promotes differentiation, expression of CoupTF1 and caudoventral fate; thus, reducing Fgf15 and Fgf8 dosage have opposite effects. Furthermore, we show that FGF15 and FGF8 differentially phosphorylate ERK (p42/44), AKT and S6 in cultures of embryonic cortex. Finally, we show that FGF15 inhibits proliferation in cortical cultures.


CONCLUSIONS
FGF15 and FGF8 have distinct signaling properties, and opposite effects on neocortical patterning and differentiation; FGF15 promotes CoupTF1 expression, represses proliferation and promotes neural differentiation.
Borello
Ugo
U
Nina Ireland Laboratory of Developmental Neurobiology, Department of Psychiatry, University of California, San Francisco, CA 94143, USA. ugo.borello@ucsf.edu
Cobos
Inma
I
Long
Jason E
JE
McWhirter
John R
JR
Murre
Cornelis
C
Rubenstein
John L R
JL
D000818:Animals; D002454:Cell Differentiation / Q000502:physiology; D002455:Cell Division / Q000502:physiology; D002478:Cells, Cultured; D002552:Cerebral Ventricles / Q000166:cytology / Q000196:embryology / Q000502:physiology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D051524:Fibroblast Growth Factor 8 / Q000235:genetics* / Q000378:metabolism*; D005346:Fibroblast Growth Factors / Q000235:genetics* / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental; D053823:Hedgehog Proteins / Q000378:metabolism; D051379:Mice; D008817:Mice, Mutant Strains; D019579:Neocortex / Q000166:cytology / Q000196:embryology / Q000502:physiology; D009474:Neurons / Q000166:cytology / Q000502:physiology; D011247:Pregnancy; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D019893:Ribosomal Protein S6 Kinases / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D014212:Tretinoin / Q000378:metabolism; D051153:Wnt Proteins / Q000378:metabolism
C496457:Fgf8 protein, mouse; D053823:Hedgehog Proteins; C465570:Shh protein, mouse; D051153:Wnt Proteins; C108526:fibroblast growth factor 15, mouse; D051524:Fibroblast Growth Factor 8; D014212:Tretinoin; D005346:Fibroblast Growth Factors; D051057:Proto-Oncogene Proteins c-akt; D019893:Ribosomal Protein S6 Kinases; D048049:Extracellular Signal-Regulated MAP Kinases