Targets of the nuclear factor I regulon involved in early and late development of postmitotic cerebellar granule neurons.
Recent studies have shown that the nuclear factor I (NFI) family controls multiple stages of the postmitotic differentiation of cerebellar granule neurons (CGNs). Regulation of cell-cell signaling is an integral part of this NFI program, which involves expression of the cell adhesion molecules N cadherin and ephrin B1 throughout postmitotic CGN development. Here, we identify two additional downstream targets of NFI that are involved in extracellular CGN interactions. The cell adhesion molecule Tag-1 is highly enriched in CGNs undergoing parallel fiber formation and is down-regulated prior to onset of radial migration. We found that Tag-1 expression was strongly reduced by NFI dominant repression in immature primary CGNs and in the cerebella of E18 Nfib-null mice. Transient transfection and chromatin immunoprecipitation suggested that the Tag-1 gene is directly regulated by NFI. Furthermore, functional, Nfi knockout and chromatin immunoprecipitation studies implicated Wnt7a as a direct target of NFI in maturing CGNs. Wnt7a is secreted by developing CGNs and is required for maturation of mossy fiber-CGN synaptic rosettes. Consistent with this, synapsin I was greatly reduced within the internal granule cell layer of P17 Nfia-null mice. These findings indicated that NFI controls CGN postmitotic maturation through a combination of extracellular signaling molecules that operate either continuously to regulate multiple stages of development (N cadherin and ephrin B1) or primarily at early (Tag-1) or late (Wnt7a) maturation steps. They also illustrate the importance of NFI as a critical link between cell-intrinsic mechanisms and cell-cell interactions in the development of the mouse cerebellum.
Wang
Wei
W
Department of Cellular and Molecular Physiology and Program in Neuroscience, University of Massachusetts Medical School, Worcester, Massachusetts 01655, USA.
Crandall
James E
JE
Litwack
E David
ED
Gronostajski
Richard M
RM
Kilpatrick
Daniel L
DL
D000818:Animals; D015820:Cadherins / Q000378:metabolism; D015816:Cell Adhesion Molecules, Neuronal / Q000378:metabolism; D002450:Cell Communication / Q000502:physiology; D002478:Cells, Cultured; D002531:Cerebellum / Q000196:embryology / Q000254:growth & development / Q000502:physiology*; D002843:Chromatin / Q000378:metabolism; D058969:Contactin 2; D036387:Ephrin-B1 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008938:Mitosis; D051839:NFI Transcription Factors / Q000235:genetics* / Q000378:metabolism; D009474:Neurons / Q000502:physiology*; D018085:Regulon; D015398:Signal Transduction; D013997:Time Factors; D051153:Wnt Proteins / Q000378:metabolism
D015820:Cadherins; D015816:Cell Adhesion Molecules, Neuronal; D002843:Chromatin; C548675:Cntn2 protein, mouse; D058969:Contactin 2; C092571:Efnb1 protein, mouse; D036387:Ephrin-B1; D051839:NFI Transcription Factors; C497646:Nfia protein, mouse; C484683:Nfib protein, mouse; D051153:Wnt Proteins; C490508:Wnt7a protein, mouse