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First published online 11 July 2007
doi: 10.1242/dev.007567

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Hox patterning of the vertebrate rib cage

¹ Division of Molecular Medicine and Genetics, Department of Internal Medicine, University of Michigan Medical Center, 109 Zina Pitcher, Ann Arbor, MI 48109-2200, USA.
² Department of Cellular and Developmental Biology, University of Michigan Medical Center, 109 Zina Pitcher, Ann Arbor, MI 48109-2200, USA.
³ Centre de Recherche en Cancérologie de l'Université Laval, Centre Hospitalier Universitaire de Québec, Québec, G1R 2J6, Canada.
⁴ Department of Human Genetics, University of Utah, and Howard Hughes Medical Institute, Salt Lake City, UT 84112, USA.

View larger version (70K): [in this window] [in a new window]   Fig. 1. Whole skeletal phenotypes from Hox5, Hox6 and Hox9 paralogous mutant mice. Lateral and ventral views of the rib cages of Hox5 (A,E), Hox6 (B,F), wild-type (C,G) and Hox9 (D,H) paralogous mutant mice at E18.5. Hox5 paralogous mutants refer to the genotype Hoxa5 -/-; Hoxb5-/-; Hoxc5-/- (Hox5aabbcc), Hox6 mutants refers to the genotype Hoxa6-/-; Hoxb6-/-; Hoxc6-/- (Hox6aabbcc), and Hox9 paralogous mutants refers to the genotype Hoxa9-/-; Hoxb9-/-; Hoxc9-/-; Hoxd9-/- (Hox9aabbccdd). In lateral views (A-D), all vertebrae having visible ribs are numbered, whereas in ventral views (E-H), only those that articulate with the sternum are numbered. The rib cages in E-H are intact (white paper inside the rib cage hides the dorsal aspects of the rib cages). The red bar in E-H provides a size reference for the length of the sternum. Black numbers indicate ribs that normally connect with the sternum, red numbers indicate extra ribs connecting to the sternum, and blue numbers indicate floating ribs. Arrows in A mark fused cervical vertebrae. Green asterisk in E marks connective tissue in place of missing manubrium and first sternabra. Orange asterisk in F denotes missing xiphoid process. Green arrowheads in G denote wild-type manubrium and first sternabra.

View larger version (48K): [in this window] [in a new window]   Fig. 2. Anterior homeotic transformations of vertebral elements in Hox5, Hox6, Hox9, Hox10 and Hox11 paralogous mutants. (A-C,F,G) Anterior views of individual vertebrae from controls (upper row) and mutants (lower row) for each set of paralogous mutants for Hox5 (A), Hox6 (B), Hox9 (C), Hox10 (F), Hox11 (G). The position of each vertebra in controls is indicated by C (cervical), T (thoracic), L (lumbar), S (sacral) or Cd (caudal), followed by a number identifying its position in each region. Vertebral elements anterior and posterior to those shown in the figure appear identical to controls. (D,E) Dorsal views of control (D) and Hox9 quadruple mutant (E) axial skeletons. In the control mouse, the sacrum is immediately caudal to six lumbar vertebrae (indicated by yellow stars on L1 and L6). In the Hox9 mutant, the lumbar region is extended by two vertebral elements. The yellow stars in E mark control positions of the first and sixth lumbar vertebrae.

View larger version (43K): [in this window] [in a new window]   Fig. 3. Rib and sternal abnormalities in the Hox5, Hox6 and Hox9 paralogous mutants. (A) Individual skeletal elements, dissected with ribs attached, from the upper thoracic region of Hox5 paralogous mutant, wild-type and Hox6 paralogous mutant mice. The first column shows the first through eighth thoracic elements from a Hox5 mutant mouse (the ventral ribs on T2 in this animal are incompletely formed). The second column depicts the same elements from a wild-type control mouse. The elements in the third column are from a Hox6 mutant (in this mouse, T3 was fused with T4, and so appears incompletely formed). Red arrows denote the rib angle of control T1 and the phenotypic similarity in Hox6 mutant T2 through T4. (B) Individual skeletal elements, with ribs attached, from the thoracic and lumbar regions of a Hox9 paralogous mutant mouse (right column) are compared with those of a wild-type control (left column).

View larger version (34K): [in this window] [in a new window]   Fig. 4. Defects in the rib cage of Hox mutant mice show functional redundancy. Ventral views of the skeletal phenotypes from wild-type (A), Hox5 five-allele (B), Hox6 five-allele (C), Hox9 seven-allele (D) and Hox5/Hox6 trans-triple heterozygous (E) mice. Numbers below the rib cage indicate the thoracic vertebrae with ribs that fuse to the sternum. The red bar is included as a size reference. Note that any combination of five mutant alleles of Hox5 or Hox6 (Aabbcc, aaBbcc and aabbCc) shows very similar phenotypes to the ones shown in B and C. In the Hox9 paralogous group, however, Hoxc9 contributes more strongly to extra sternal rib growth and fusion than the other Hox9 genes (data not shown).

View larger version (112K): [in this window] [in a new window]   Fig. 5. Hox expression during axial patterning. The anterior boundary of Hoxb6 expression at E11.5 is the same in control (A) and Hox5 paralogous mutant (B) mice. The anterior boundary of Hoxd11 expression in control (C) and Hox10 paralogous mutants (D) is also equivalent. (E-M) A Neor probe was used to demonstrate the anterior expression boundaries of the entire paralogous group in triple heterozygous animals (in the case of Hox5 and Hox6 embryos) or quadruple heterozygous mutants (for Hox9 embryos), none of which have a phenotype. Each mutant allele has Neor inserted into the Hox coding sequence. Somite anterior expression limits are marked with a white arrow and lateral plate anterior expression limits are marked with a black arrow. (The anterior expression limit for the neural tube, marked with a black arrowhead, is often far anterior to the somite expression boundary as published for the individual Hox genes referenced in the text.) E,F,H,I,K,L, embryos shown in lateral and dorsal view; G,J,M, embryos shown in lateral view only.

View larger version (42K): [in this window] [in a new window]   Fig. 6. Schematic representation of paralogous Hox axial skeleton phenotypes. Somite-derived, primaxial skeletal elements that exhibit anterior homeotic transformations in paralogous mutants are in red. Lateral plate-derived structures affected in paralogous mutants are in blue. Note that Hox5, Hox6 and Hox9 mutant phenotypes are offset in their AP extent for defects in the somite-derived (red) and lateral plate-derived (blue) skeleton. The yellow shading highlights somite-derived AP regions that are affected in adjacent paralogous mutant groups. In each case, the overlapping regions of phenotype display distinct vertebral morphologies for each paralogous mutant. The green asterisks in the Hox9 mutant reflect the posterior shift of the axial skeleton. Mice normally possess 28-30 caudal vertebrae. Only 15 are represented here for simplicity. Despite changes in the number of caudal vertebrae in Hox9 and Hox11 paralogous mutants, the same average total numbers of vertebrae are present in all of the paralogous mutants depicted in this diagram, and are the same as in control animals.

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