On 2015 Mar 27, KLAUS KAESTNER commented:

Dear Dr. Tarlow We are well aware of the fact that a CreER is required for genetic lineage tracing. We tried many times to derive a Foxl1-CreER line. Unfortunately, none of our six founders showed any expression. We will keep trying!

In the case of Foxl1 expression in the liver, there is an additional difficulty to consider. There are no Foxl1 expressing cell in the healthy, uninjured liver. Thus, even a Foxl1-CreER does not help, as it will not label any cell! The Foxl1 promoter becomes activated only AFTER specific types of liver injury.

Note that additional evidence for the bi-lineage potential of Foxl1-Cre marked cells comes from the fact that one can establish clones of cells from a SINGLE Foxl1-Cre/RosaYFP labelled cell, and these can be expanded indefinitely. Thus, these cells are clonogenic. In vitro, these cells can be differentiated towards both the cholangiocyte and hepatocyte lineage.

Note also that we acknowledge the limitations of our current model in the discussion of this paper. Klaus Kaestner

On 2014 Dec 23, Branden David Tarlow commented:

It's unclear why this group has not replicated their results with the Foxl1-Cre with a CreERT2 allele since the original 2009 publication. I agree with a recent review that stated "Experiments using non-inducible Cre lines do not constitute bona fide lineage tracing tools..." (see Lemaigre Hepatology 2014; doi: 10.1002/hep.27659)

On 2014 Dec 23, Branden David Tarlow commented:

It's unclear why this group has not replicated their results with the Foxl1-Cre with a CreERT2 allele since the original 2009 publication. I agree with a recent review that stated "Experiments using non-inducible Cre lines do not constitute bona fide lineage tracing tools..." (see Lemaigre Hepatology 2014; doi: 10.1002/hep.27659)

On 2015 Mar 27, KLAUS KAESTNER commented:

Dear Dr. Tarlow We are well aware of the fact that a CreER is required for genetic lineage tracing. We tried many times to derive a Foxl1-CreER line. Unfortunately, none of our six founders showed any expression. We will keep trying!

In the case of Foxl1 expression in the liver, there is an additional difficulty to consider. There are no Foxl1 expressing cell in the healthy, uninjured liver. Thus, even a Foxl1-CreER does not help, as it will not label any cell! The Foxl1 promoter becomes activated only AFTER specific types of liver injury.

Note that additional evidence for the bi-lineage potential of Foxl1-Cre marked cells comes from the fact that one can establish clones of cells from a SINGLE Foxl1-Cre/RosaYFP labelled cell, and these can be expanded indefinitely. Thus, these cells are clonogenic. In vitro, these cells can be differentiated towards both the cholangiocyte and hepatocyte lineage.

Note also that we acknowledge the limitations of our current model in the discussion of this paper. Klaus Kaestner