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Targeted Deletion of Btg1 and Btg2 Results in Homeotic Transformation of the Axial Skeleton.

Tijchon E, van Ingen Schenau D, van Opzeeland F, Tirone F, Hoogerbrugge PM, Van Leeuwen FN, Scheijen B - PLoS ONE (2015)

Bottom Line: Loss of Btg2, but not Btg1, was sufficient for complete posterior transformation of the thirteenth thoracic vertebra to the first lumbar vertebra.The Btg1-/-;Btg2-/- animals showed an even stronger phenotype, with L5 to S1 transformation.Together, these data show that both Btg1 and Btg2 are required for normal vertebral patterning of the axial skeleton, but each gene contributes differently in specifying the identity along the anterior-posterior axis of the skeleton.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Pediatric Oncology, Radboud university medical center, Nijmegen, The Netherlands.

ABSTRACT
Btg1 and Btg2 encode highly homologous proteins that are broadly expressed in different cell lineages, and have been implicated in different types of cancer. Btg1 and Btg2 have been shown to modulate the function of different transcriptional regulators, including Hox and Smad transcription factors. In this study, we examined the in vivo role of the mouse Btg1 and Btg2 genes in specifying the regional identity of the axial skeleton. Therefore, we examined the phenotype of Btg1 and Btg2 single knockout mice, as well as novel generated Btg1-/-;Btg2-/- double knockout mice, which were viable, but displayed a non-mendelian inheritance and smaller litter size. We observed both unique and overlapping phenotypes reminiscent of homeotic transformation along the anterior-posterior axis in the single and combined Btg1 and Btg2 knockout animals. Both Btg1-/- and Btg2-/- mice displayed partial posterior transformation of the seventh cervical vertebra, which was more pronounced in Btg1-/-;Btg2-/- mice, demonstrating that Btg1 and Btg2 act in synergy. Loss of Btg2, but not Btg1, was sufficient for complete posterior transformation of the thirteenth thoracic vertebra to the first lumbar vertebra. Moreover, Btg2-/- animals displayed complete posterior transformation of the sixth lumbar vertebra to the first sacral vertebra, which was only partially present at a low frequency in Btg1-/- mice. The Btg1-/-;Btg2-/- animals showed an even stronger phenotype, with L5 to S1 transformation. Together, these data show that both Btg1 and Btg2 are required for normal vertebral patterning of the axial skeleton, but each gene contributes differently in specifying the identity along the anterior-posterior axis of the skeleton.

No MeSH data available.


Related in: MedlinePlus

Posterior homeotic transformation of the thirteenth thoracic vertebra in mice deficient for Btg2.(A-D) Dorsal view of the cervicothoracic region of the skeleton in 18.5 dpc wild-type, Btg1-/-, Btg2-/- and Btg1-/-;Btg2-/- embryos stained with alizarin red and alcian blue. (A-B) Wild-type C57BL6/J mice have thirteen thoracic ribs, while Btg1-deficient mice display fourteen ribs due to the extra extensive rib at C7. (D) Although the T13 rib is absent in Btg1-/-;Btg2-/- mice they still have thirteen thoracic ribs due to the C7 to T1 posterior transformation.
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pone.0131481.g004: Posterior homeotic transformation of the thirteenth thoracic vertebra in mice deficient for Btg2.(A-D) Dorsal view of the cervicothoracic region of the skeleton in 18.5 dpc wild-type, Btg1-/-, Btg2-/- and Btg1-/-;Btg2-/- embryos stained with alizarin red and alcian blue. (A-B) Wild-type C57BL6/J mice have thirteen thoracic ribs, while Btg1-deficient mice display fourteen ribs due to the extra extensive rib at C7. (D) Although the T13 rib is absent in Btg1-/-;Btg2-/- mice they still have thirteen thoracic ribs due to the C7 to T1 posterior transformation.

Mentions: The rib pairs derived from T8 to T13 are termed “false ribs”, since they do not connect to the sternum. Instead, the T8 to T11 ribs form cartilaginous connections with the adjacent ribs, while T12 and T13 are considered floating ribs, since they form no connections to adjacent rib pairs (Fig 4A). Deletion of Btg1 resulted in fourteen thoracic ribs in 62% of mice, as a consequence of the extra rib at C7, without any evidence of posterior transformation at the thoracic-lumbar junction (Fig 4B/Table 3). In contrast, mice deficient for Btg2 displayed thirteen thoracic ribs as they acquired an extra rib at C7, while the thirteenth rib (T13) was often rudimentary or completely absent and acquired the identity of the first lumbar vertebra (L1) (Table 3). As a consequence, most Btg2-/- mice showed only twelve thoracic ribs compared to thirteen in wild-type animals, and all Btg2-/- mice displayed posterior homeotic transformation at the thoracic-lumbar junction (Fig 4C). Mice deficient for both Btg1 and Btg2 expression showed again normal numbers of thoracic ribs in 95% of the animals, since these mice displayed both C7 to T1 and T13 to L1 posterior transformations (Fig 4D/Table 3). These data demonstrate a unique function for Btg2 in regulating the regional identity of vertebra at the thoracic to lumbar transition.


Targeted Deletion of Btg1 and Btg2 Results in Homeotic Transformation of the Axial Skeleton.

Tijchon E, van Ingen Schenau D, van Opzeeland F, Tirone F, Hoogerbrugge PM, Van Leeuwen FN, Scheijen B - PLoS ONE (2015)

Posterior homeotic transformation of the thirteenth thoracic vertebra in mice deficient for Btg2.(A-D) Dorsal view of the cervicothoracic region of the skeleton in 18.5 dpc wild-type, Btg1-/-, Btg2-/- and Btg1-/-;Btg2-/- embryos stained with alizarin red and alcian blue. (A-B) Wild-type C57BL6/J mice have thirteen thoracic ribs, while Btg1-deficient mice display fourteen ribs due to the extra extensive rib at C7. (D) Although the T13 rib is absent in Btg1-/-;Btg2-/- mice they still have thirteen thoracic ribs due to the C7 to T1 posterior transformation.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4517811&req=5

pone.0131481.g004: Posterior homeotic transformation of the thirteenth thoracic vertebra in mice deficient for Btg2.(A-D) Dorsal view of the cervicothoracic region of the skeleton in 18.5 dpc wild-type, Btg1-/-, Btg2-/- and Btg1-/-;Btg2-/- embryos stained with alizarin red and alcian blue. (A-B) Wild-type C57BL6/J mice have thirteen thoracic ribs, while Btg1-deficient mice display fourteen ribs due to the extra extensive rib at C7. (D) Although the T13 rib is absent in Btg1-/-;Btg2-/- mice they still have thirteen thoracic ribs due to the C7 to T1 posterior transformation.
Mentions: The rib pairs derived from T8 to T13 are termed “false ribs”, since they do not connect to the sternum. Instead, the T8 to T11 ribs form cartilaginous connections with the adjacent ribs, while T12 and T13 are considered floating ribs, since they form no connections to adjacent rib pairs (Fig 4A). Deletion of Btg1 resulted in fourteen thoracic ribs in 62% of mice, as a consequence of the extra rib at C7, without any evidence of posterior transformation at the thoracic-lumbar junction (Fig 4B/Table 3). In contrast, mice deficient for Btg2 displayed thirteen thoracic ribs as they acquired an extra rib at C7, while the thirteenth rib (T13) was often rudimentary or completely absent and acquired the identity of the first lumbar vertebra (L1) (Table 3). As a consequence, most Btg2-/- mice showed only twelve thoracic ribs compared to thirteen in wild-type animals, and all Btg2-/- mice displayed posterior homeotic transformation at the thoracic-lumbar junction (Fig 4C). Mice deficient for both Btg1 and Btg2 expression showed again normal numbers of thoracic ribs in 95% of the animals, since these mice displayed both C7 to T1 and T13 to L1 posterior transformations (Fig 4D/Table 3). These data demonstrate a unique function for Btg2 in regulating the regional identity of vertebra at the thoracic to lumbar transition.

Bottom Line: Loss of Btg2, but not Btg1, was sufficient for complete posterior transformation of the thirteenth thoracic vertebra to the first lumbar vertebra.The Btg1-/-;Btg2-/- animals showed an even stronger phenotype, with L5 to S1 transformation.Together, these data show that both Btg1 and Btg2 are required for normal vertebral patterning of the axial skeleton, but each gene contributes differently in specifying the identity along the anterior-posterior axis of the skeleton.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Pediatric Oncology, Radboud university medical center, Nijmegen, The Netherlands.

ABSTRACT
Btg1 and Btg2 encode highly homologous proteins that are broadly expressed in different cell lineages, and have been implicated in different types of cancer. Btg1 and Btg2 have been shown to modulate the function of different transcriptional regulators, including Hox and Smad transcription factors. In this study, we examined the in vivo role of the mouse Btg1 and Btg2 genes in specifying the regional identity of the axial skeleton. Therefore, we examined the phenotype of Btg1 and Btg2 single knockout mice, as well as novel generated Btg1-/-;Btg2-/- double knockout mice, which were viable, but displayed a non-mendelian inheritance and smaller litter size. We observed both unique and overlapping phenotypes reminiscent of homeotic transformation along the anterior-posterior axis in the single and combined Btg1 and Btg2 knockout animals. Both Btg1-/- and Btg2-/- mice displayed partial posterior transformation of the seventh cervical vertebra, which was more pronounced in Btg1-/-;Btg2-/- mice, demonstrating that Btg1 and Btg2 act in synergy. Loss of Btg2, but not Btg1, was sufficient for complete posterior transformation of the thirteenth thoracic vertebra to the first lumbar vertebra. Moreover, Btg2-/- animals displayed complete posterior transformation of the sixth lumbar vertebra to the first sacral vertebra, which was only partially present at a low frequency in Btg1-/- mice. The Btg1-/-;Btg2-/- animals showed an even stronger phenotype, with L5 to S1 transformation. Together, these data show that both Btg1 and Btg2 are required for normal vertebral patterning of the axial skeleton, but each gene contributes differently in specifying the identity along the anterior-posterior axis of the skeleton.

No MeSH data available.


Related in: MedlinePlus