Protease nexin 1 and its receptor LRP modulate SHH signalling during cerebellar development.
Development of the postnatal cerebellum relies on the tight regulation of cell number by morphogens that control the balance between cell proliferation, survival and differentiation. Here, we analyze the role of the serine-protease inhibitor protease nexin 1 (PN-1; SERPINE2) in the proliferation and differentiation of cerebellar granular neuron precursors (CGNPs) via the modulation of their main mitogenic factor, sonic hedgehog (SHH). Our studies show that PN-1 interacts with low-density lipoprotein receptor-related proteins (LRPs) to antagonize SHH-induced CGNP proliferation and that it inhibits the activity of the SHH transcriptional target GLI1. The binding of PN-1 to LRPs interferes with SHH-induced cyclin D1 expression. CGNPs isolated from Pn-1-deficient mice exhibit enhanced basal proliferation rates due to overactivation of the SHH pathway and show higher sensitivity to exogenous SHH. In vivo, the Pn-1 deficiency alters the expression of SHH target genes. In addition, the onset of CGNP differentiation is delayed, which results in an enlarged outer external granular layer. Furthermore, the Pn-1 deficiency leads to an overproduction of CGNPs and to enlargement of the internal granular layer in a subset of cerebellar lobes during late development and adulthood. We propose that PN-1 contributes to shaping the cerebellum by promoting cell cycle exit.
Vaillant
Catherine
C
Friedrich Miescher Institute for Biomedical Research, Maulbeerstrasse 66, Basel, Switzerland.
Michos
Odyssé
O
Orolicki
Slobodanka
S
Brellier
Florence
F
Taieb
Sabrina
S
Moreno
Eliza
E
Té
Hélène
H
Zeller
Rolf
R
Monard
Denis
D
D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002478:Cells, Cultured; D002531:Cerebellum / Q000254:growth & development* / Q000378:metabolism; D005260:Female; D053823:Hedgehog Proteins / Q000378:metabolism*; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D058255:Protease Nexins; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism*; D011973:Receptors, LDL / Q000378:metabolism*; D015398:Signal Transduction; D025521:Tumor Suppressor Proteins / Q000378:metabolism*
D016564:Amyloid beta-Protein Precursor; D053823:Hedgehog Proteins; D026503:Low Density Lipoprotein Receptor-Related Protein-1; C486645:Lrp1 protein, mouse; D058255:Protease Nexins; D011956:Receptors, Cell Surface; D011973:Receptors, LDL; C465570:Shh protein, mouse; D025521:Tumor Suppressor Proteins