Dr. James Briscoe

Role of hedgehog signaling during neural tube development

Dessaud E, Yang LL, Hill K, Cox B, Ulloa F, Ribeiro A, Mynett A, Novitch BG, Briscoe J. 2007. Interpretation of the sonic hedgehog morphogen gradient by a temporal adaptation mechanism. Nature. 450(7170):717-20.

Dessaud, McMahon, and Briscoe. 2008. Pattern formation in the vertebrate neural tube: a sonic hedgehog morphogen-regulated transcriptional network. Development 135, 2489-2503.

Vanessa Ribes and James Briscoe. 2009. Establishing and Interpreting Graded Sonic Hedgehog Signaling during Vertebrate Neural Tube Patterning: The Role of Negative Feedback. Cold Spring Harb Perspect Biol. 1:a002014

Question 1

Briefly tell us a bit about yourselves, your career paths over the years, and specifically what led you to begin working on the role of hedgehog signaling during neural tube development.

Michael Barresi

Question 2

Can you please frame our discussion today by briefly detailing your working model of the role of Hedgehog signaling in patterning cell fate in the neural tube?

Jiyun Seo

Question 3

It was deduced that the profile of GLI activity evoked by SHH is shaped mainly by an adaptation mechanism acting upstream of SMO, and PTC 1 was introduced as an inhibitor of SHH signalling. Are there any other possible inhibitors or transmembrane components that can also act as an inhibitor of SHH signaling that can possibly shape the GLI profile of activity upstream of SMO other than PTC 1? Is it possible that this factor can also have cell autonomous and non-autonomous functions in morphogen interpretation?

Rachel Lackert

Question 4

Does Patched1 set a time period for exposure based on SHH concentration for a cell? If so, does it use its inhibitory function to sequester SHH after the time period is up, or is SHH signaling merely ‘used up’?

Lucy Ye

Question 5

How can the differentiation of a cell to Shh be at all concentration dependent if 1nm and 4nm produce the same gli activation and further gli activation does not affect nkx differentiation?

Alexandra Sobhani

Question 6

Why would Shh accumulate within a cell when it is a surface-binding signal? What is the purpose of internalizing the Shh ligand?

Elizabeth Greenwood

Question 7

Figure 2a shows Pax7, Olig2 and Nkx2.2 expression in HH stage 19 in a chick neural tube. At this stage the expression of these transcription factors is very distinct from each other and there does not appear to be areas of coexpression. How does that work when SHH itself is in a gradient.

Alyssa Zachariah

Question 8

Is NKX2.2 only expressed in cells that previously expressed OLIG2? If so and when paired with current data that NKX2.2 is expressed after Olig 2 and NKX2.2 is affected by changes in Olig2 expression, then does it suggest Olig2 is necessary for the expression of NKX2.2?

Uzuri Sims

Question 9

At about 0.25 nM, Pax7 expression is almost gone. Is this loss of expression of Pax7 also dependent on the duration of exposure to Shh? Also, is there a mechanism that allows dorsal cells to become desensitized to ongoing Shh signaling, similar to the way Olig2 and NKX2.2-expressing cells become desensitized?

Allison Ulrich

Question 10

Are dorsally secreted BMP signals also interpreted based both on concentration and time of exposure as you showed for the ventrally secreted Shh signal?

Katy Frank

Question 11

This was mentioned at the end of Pattern Formation in the vertebrate… – if you can expand/comment on how cells integrate the effects of multiple co-incident signals (BMP and Wnt signaling).

Catherine Castillo

Question 12

Currently in your opinion what are the most pressing questions in the study of Neural Tube patterning and Hedgehog signaling, and what steps is your lab taking to address these questions?

Michael J.F. Barresi