It has been observed by Dale et al. (2003) that constitutive misexpression of L-fng in the PSM blocks the somitogenesis clock, and suppresses the expression of endogenous L-fng. This has been interpreted by the authors as supporting the existence of a negative feedback circuit between L-fng and Notch signalling: Notch signalling would activate L-fng transcription, and L-fng would down-regulate Notch-signalling; this circuit would be the core of the somitogenesis clock. However, while it has been demonstrated that L-fng transcription is indeed activated by Notch signalling (Morales et al., 2002, Cole et al., 2002, confirmed by other means by Dale et al., 2003), L-fng-induced down-regulation of Delta-mediated Notch signalling is contrary to present biological evidence, which shows L-fng-catalysed glycosylation to make the Notch receptor more sensitive to activation by Delta (Blair, 2000) (of the two Notch ligands Delta and Serrate, only Delta is expressed in the chick up to the first somite stage, Caprioli et al., 2002).
What's more, suppression of endogenous L-fng expression by misexpression of L-fng does not imply that the oscillations rely exclusively on a negative-feedback circuit. In the L-fng secretion model, for a single cell there are 4 feedback circuits between the 3 variables, one of which (between L-fng and sensitised Notch) is positive and essential for the oscillations. If the model is modified to account for misexpression of L-fng, and if the misexpression strength is above a threshold, oscillations are stopped and L-fng is endogenously expressed at a dramatically lower intensity (data not shown). The intuitive reason for this is that continuous L-fng expression depletes the pool of un-sensitised Notch; in the model, sensitised Notch has a shorter half-life than Notch, and even though it is continuously produced if L-fng is continuously expressed, its concentration is much lower than its peak concentration when it is produced in bursts.
The L-fng secretion model is thus compatible with the data reported by Dale et al. (2003), as well as with the data on sensitisation of Notch by L-fng.
In contrast to Dale et al. (2003), Serth et al. (2003) reported that misexpression of L-fng in mouse PSM does not suppress endogenous oscillations, but disrupts their pattern. A major difference between the method employed by the two groups is that Dale et al. (2003) electroporated plasmids carrying l-fng under the control of a strong, constitutive promoter, while Serth et al. (2003) created transgenic mice with l-fng under the control of a portion of the delta promoter. It is thus quite possible that a stronger level of misexpression was achieved by Dale et al. (2003). The L-fng secretion model can reconcile both results, because suppression of endogenous oscillations is only achieved above a threshold level of misexpression, comparable to the amplitude of endogenous oscillations; what's more, the amplitude of the endogenous oscillations is reduced by misexpression, as reported by Serth et al. (2003) (however, it was not possible to reproduce the disappearance of oscillations specifically in the anterior PSM).