Mouse cells can regulate genes from fish
Since both mice and zebrafish have well-developed nervous systems (not as good as humans but definitely better than a worm), they both have a need for Sox10 to help neural crest cells specialize.
The Sox10 in zebrafish does not look exactly the same as the gene in mice, but there are still some sequences that they have in common. These conserved sequences are probably a clue to the core function of Sox10.
The investigators discovered that the regulatory sequences from mice actually would control the expression of the Sox10 gene in zebrafish. This is interesting because zebrafish do not have regulatory sequences that look like the ones in mice.
"As we have seen before, genes often possess many regulatory sequences with overlapping function - suggesting that gene activation is not a binary (ON/OFF) event. Zebrafish provided fantastic and accurate insight into the way these sequences functioned when we tested them in mice," McCallion said.
There were two regulatory fragments in particular that seemed to be the most important in regulating Sox10. These were Sox10-MCS4 and Sox10-MCS7, where MCS stands for multiple-species conserved sequences.
These two fragments, if deleted, led to a reduction in gene expression of Sox10. Not only are these regulatory sequences, but they actually enhance the expression of Sox10 when present in their complete form.
It was also discovered that certain sequence fragments led to very specific control over one type of cell. For example, Sox10-MCS7 may be most important for pigment cells rather than other neural crest cells. If this region is deleted, the mouse exhibits hypopigmentation. So a given regulatory sequence may be used more for certain cells than others.
However, the biggest finding from this research is that Sox10 is an enhancer for all neural crest-derived cell types. It is important in pigment cells, neurons in the peripheral nervous system and glial cells.
Mutations in this gene lead to major problems in development of these systems.
"We have shown in this and other studies that regulatory sequences likely utilize a vocabulary that distinguishes their functions," McCallion said. "This will begin to guide our search for disease risk mutations in the human populations."
"The goal is to be able to say a priori, 'We are interested in genes that are used in cell X at time Y or in response to stimulus Z.' and select the corresponding sequences from the genome for analysis in patients and unaffected individuals to look for differences that correlate with disease so we can evaluate their impact."
The Sox10 in zebrafish does not look exactly the same as the gene in mice, but there are still some sequences that they have in common. These conserved sequences are probably a clue to the core function of Sox10.
The investigators discovered that the regulatory sequences from mice actually would control the expression of the Sox10 gene in zebrafish. This is interesting because zebrafish do not have regulatory sequences that look like the ones in mice.
"As we have seen before, genes often possess many regulatory sequences with overlapping function - suggesting that gene activation is not a binary (ON/OFF) event. Zebrafish provided fantastic and accurate insight into the way these sequences functioned when we tested them in mice," McCallion said.
There were two regulatory fragments in particular that seemed to be the most important in regulating Sox10. These were Sox10-MCS4 and Sox10-MCS7, where MCS stands for multiple-species conserved sequences.
These two fragments, if deleted, led to a reduction in gene expression of Sox10. Not only are these regulatory sequences, but they actually enhance the expression of Sox10 when present in their complete form.
It was also discovered that certain sequence fragments led to very specific control over one type of cell. For example, Sox10-MCS7 may be most important for pigment cells rather than other neural crest cells. If this region is deleted, the mouse exhibits hypopigmentation. So a given regulatory sequence may be used more for certain cells than others.
However, the biggest finding from this research is that Sox10 is an enhancer for all neural crest-derived cell types. It is important in pigment cells, neurons in the peripheral nervous system and glial cells.
Mutations in this gene lead to major problems in development of these systems.
"We have shown in this and other studies that regulatory sequences likely utilize a vocabulary that distinguishes their functions," McCallion said. "This will begin to guide our search for disease risk mutations in the human populations."
"The goal is to be able to say a priori, 'We are interested in genes that are used in cell X at time Y or in response to stimulus Z.' and select the corresponding sequences from the genome for analysis in patients and unaffected individuals to look for differences that correlate with disease so we can evaluate their impact."
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