Tbx10 causes cleft palate

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Tbx10 causes cleft palate

Results point to an unexpected link between smoking and cleft lip and palate

| By Cathy Holding

Researchers have found a gene that causes cleft lip and palate in mice,

according to a paper in the April 26 PNAS. The finding also suggests a

causal link between smoking and cleft lip and palate in humans, say the

authors.

Although many cleft palate mouse models exist, cleft lip is rare in mice.

The Dancer mutation causes the rarer cleft lip and palate (CL/P), and

identification and characterization of this mutation could provide a model

to study the molecular pathways involved in both normal craniofacial

development and CL/P pathogenesis, lead researcher Rulang Jiang, professor

of biology at the University of Rochester, NY, told The Scientist.

Dancer is a mutation not studied since the 1950s, which meant that live mice

had to be generated from frozen embryos. The team mapped Dancer to a 1-cM

region near the centromere of chromosome 19, and in situ hybridization

studies showed that one positional candidate gene, T-box transcription

factor Tbx10, is ectopically expressed in Dancer mutants.

³We picked a few genes including this one, Tbx10. It looked interesting as a

candidate for the cleft mutation is because there are a few other T-box

family genes related in sequence that are involved in human developmental

disorders,² said Jiang.

However, Tbx1 and Tbx22, which also cause cleft lip and palate in man, are

deletion mutations, and because Tbx10 is not expressed in mouse embryos

except in the hindbrain, the team initially dismissed the gene. ³One day we

discussed it‹we were fed up‹let's look at whether the Dancer mutants have

altered expression of Tbx10; the reason behind that was we knew that T-box

genes have a dose-dependent response,² said Jiang.

The authors found that a 5' region of the p23 gene had been inserted into

the first intron of Tbx10, according to Francis H. Ruddle, professor of

molecular, cellular, and developmental biology at Yale University. ³I think

the authors have made a good case for a translocation at the Tbx10 gene

altering the expression patterns of that gene, especially with regard to

ectopic expression and very possibly overexpression,² said Ruddle, who

edited the paper for PNAS but who was not involved in the study. ³I think

they've established an animal model which could be used to get more insight

into the mechanism by which cleft palate is induced.²

Martyn Cobourne, senior lecturer at the Department of Orthodontics at Guys

Hospital, London, told The Scientist, ³The net result is that you get

overexpression of Tbx10 all the way through the mouse. It just so happens

that in the facial regions for some reason it is having a major effect.²

The group modeled the natural mutant with a transgene, said Cobourne, who

was not involved in the study. ³That's quite clever. They used a different

promoter but one they knew would express Tbx10 pretty well ubiquitously, so

they've got a good substitute for their natural mutant‹and surprise,

surprise­the transgenic mouse had a cleft lip and palate.²

Cobourne said it was ³quite interesting² that the authors observed that the

heterozygous Dancer mutants, although exhibiting no native phenotype, were

more susceptible to a chemically induced form of clefting. ³It reflects, I

suspect, what happens in human populations,² he said, explaining that a

particular mutation could make an embryo more susceptible to certain

environmental effects, such as a mother smoking during pregnancy.

³If a child has that particular mutation, the mum smoking five cigarettes

per day might just be enough to tip the balance‹and that child might have a

cleft of the lip and palate,² Cobourne said.

Jiang agreed that there might be some significance to this observation. ³In

fact, the Dancer mutation interacts with the nicotine analog

6-aminonicotinamide,² he said.

Links for this article

J. Bush et al., ³The cleft lip and palate defects in Dancer mutant mice

result from gain of function of the Tbx10 gene,² PNAS,

doi:10.1073/pnas.0401025101, April 26, 2004.

http://www.pnas.org/ 

M.S. Deol, P.W. Lane, ³A new gene affecting the morphogenesis of the

vestibular part of the inner ear in the mouse,² Journal of Embryology and

Experimental Morphology, 16:543-581, December 1966.

[PubMed Abstract]  

Rulang Jiang

http://www.urmc.rochester.edu/GEBS/faculty/Rulang_Jiang.htm 

Francis H. Ruddle

http://www.biology.yale.edu/facultystaff/ruddle.html 

Martyn Cobourne

http://www.kcl.ac.uk/depsta/dentistry/research/cobpro.html