Figure 4

Biological diagram for the multiple signaling events underlying VPC specification. Biological diagram for the multiple regulatory signaling pathways underlying VPC fate specification. Three VPCs (they can be P6.p, P7.p and P8.p, or P6.p, P5.p and P4.p) according to the relative distance to the AC are selected to depict the signaling crosstalk. In the rightmost cell, the EGF/MAPK pathway cannot be activated because the induced signal (indicated by a grey line) received by LET-23, is lower than the threshold for induction, and the VPC hence adopts the 3° fate. The induction signal with high concentration (indicated by a heavy black line) activates the EGF/MAPK pathway and causes the 1° fate. It also has been known that two transcription factors, LIN-31 and LIN-1 are likely to be the downregulation targets of the MAPK pathway [42]. Both LIN-31 and LIN-1 can be phosphorylated by MAPK kinase MPK-1. LIN-31 and LIN-1 usually form a complex that is disrupted by the phosphorylation of LIN-31, and LIN-1 dissociates from LIN-31 to let LIN-31 play a role in the proper specification of VPCs. On the other hands, ligands for LIN-12 are members of the "DSL" family, an acronym derived from canonical ligands from Drosophila (D elta, S errate) and C. elegans (L AG-2). Binding of DSL ligands to LIN-12/Notch leads to the shedding of the LIN-12/Notch ectodomain (extracellular domain) via cleavage. The remaining transmembrane protein is cleaved constitutively, and the intracellular domain translocates to the nucleus, binding to the LAG-1 that usually exists as a transcription factor to repress lst genes. With the binding to LAG-1, lst genes expresses LST proteins to counteract the operations of EGF/MAPK pathways by inhibiting VPCs from becoming the 1° fate. For the details of LIN-12/Notch signaling in C. elegans, the readers are suggested to refer to [34].