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Axial and appendicular skeletal transformations, ligament alterations, and motor neuron loss in Hoxc10 mutants.

Hostikka SL, Gong J, Carpenter EM - Int. J. Biol. Sci. (2009)

Bottom Line: We have identified patterning defects resulting from the targeted mutation of Hoxc10, a member of the Hox10 paralogous family.Our results also suggest a general role for Hoxc10 in regulating chondrogenesis and osteogenesis in the hindlimb, along with a specific role in shaping femoral architecture.These results suggest a role for Hoxc10 in generating or maintaining the normal complement of lumbar motor neurons.

View Article: PubMed Central - PubMed

Affiliation: Department of Psychiatry and Biobehavioral Science, UCLA School of Medicine, Los Angeles, CA 90095, USA.

ABSTRACT
Vertebrate Hox genes regulate many aspects of embryonic body plan development and patterning. In particular, Hox genes have been shown to regulate regional patterning of the axial and appendicular skeleton and of the central nervous system. We have identified patterning defects resulting from the targeted mutation of Hoxc10, a member of the Hox10 paralogous family. Hoxc10 mutant mice have skeletal transformations in thoracic, lumbar, and sacral vertebrae and in the pelvis, along with alterations in the bones and ligaments of the hindlimbs. These results suggest that Hoxc10, along with other members of the Hox10 paralogous gene family, regulates vertebral identity at the transition from thoracic to lumbar and lumbar to sacral regions. Our results also suggest a general role for Hoxc10 in regulating chondrogenesis and osteogenesis in the hindlimb, along with a specific role in shaping femoral architecture. In addition, mutant mice have a reduction in lumbar motor neurons and a change in locomotor behavior. These results suggest a role for Hoxc10 in generating or maintaining the normal complement of lumbar motor neurons.

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Vertebral phenotypes in Hoxc10 mutants. Arrows in panels A and B illustrate the position of the transitional vertebra in wild-type and mutant animals, respectively. There is a rudimentary rib on the T13 vertebra (open arrowhead in B). Thoracic and sacral vertebral shapes are illustrated in panels C and D. The position of the costal facet, marked by arrows in C, denotes the transitional vertebra. Panel D illustrates the morphology of the sacral vertebrae. The transverse processes of the mutant S3* vertebra (bottom row) have an intermediate shape.
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Figure 4: Vertebral phenotypes in Hoxc10 mutants. Arrows in panels A and B illustrate the position of the transitional vertebra in wild-type and mutant animals, respectively. There is a rudimentary rib on the T13 vertebra (open arrowhead in B). Thoracic and sacral vertebral shapes are illustrated in panels C and D. The position of the costal facet, marked by arrows in C, denotes the transitional vertebra. Panel D illustrates the morphology of the sacral vertebrae. The transverse processes of the mutant S3* vertebra (bottom row) have an intermediate shape.

Mentions: The lack of a functional Hoxc10 homeobox causes several homeotic transformations in the axial skeleton (Table 1, Figures 3 and 4). Wild-type C57Bl/6 mice typically have 30 precaudal vertebrae, with the more caudal vertebrae organized in T13L6S4 pattern, with thirteen thoracic vertebrae, six lumbar vertebrae and four sacral vertebrae 10, 11. Eighty percent of the wild-type mice examined in this study exhibited this pattern, with the remainder of the animals showing some mild variation in the shape of the L1, L6, or S1 segments; these types of variations are within the range of normal (10. Hoxc10 mutant mice also have 30 precaudal vertebrae, but the patterning of the vertebral column is altered. Most Hoxc10 mutant mice (33 of 34 examined) show a partial to complete transformation of the thirteenth thoracic vertebrae, precaudal vertebra 20 (PC20) into a lumbar identity, typified by the reduction or complete loss of the thirteenth rib. By definition, thoracic vertebrae are those vertebrae with attached ribs; hence loss of the thirteenth rib suggests a posterior transformation of the most caudal thoracic vertebra into a lumbar identity. The most caudal lumbar vertebra (PC25) often undergoes a similar transformation into a sacral (S1) identity (Figures 3 and 4). The sacrum in wild-type animals is typically comprised of four vertebrae. The first two vertebrae, S1 and S2, have butterfly-shaped, fused transverse processes. The next two sacral vertebrae, S3 and S4, have transverse processes that are not fused, with S3 having butterfly-shaped transverse processes and S4 having club-shaped transverse processes similar to those seen on more caudal vertebrae (Figures 2 and 3). In Hoxc10 mutant animals, the fourth sacral vertebra (S3* in Figures 3 and 4) exhibits an intermediate shape between a normal S3 and S4, and there are usually five sacral-like vertebrae, three fused and two free. This suggests an anterior transformation of the first caudal vertebra into a sacral identity. This transformation restores the register of the vertebral column and thus there is no overall loss of precaudal vertebrae. In combination, these alterations produce a T12(T13/L1)L5S5 pattern in 94% of mutant mice. Heterozygous mice show several intermediate patterns, most commonly T13L5S5 (31.5%) or T12(T13/L1)L5S5 (38.9%), suggesting dosage compensation. The transitional vertebra, defined as the most anterior vertebra to show a lumbar rather than a thoracic articulation between the pre- and postzygapophyses [28 and references therein] is normally the tenth thoracic vertebra (T10), whereas in the homozygous Hoxc10 mutants the transition occurs at the ninth thoracic vertebra (T9) (Figure 4).


Axial and appendicular skeletal transformations, ligament alterations, and motor neuron loss in Hoxc10 mutants.

Hostikka SL, Gong J, Carpenter EM - Int. J. Biol. Sci. (2009)

Vertebral phenotypes in Hoxc10 mutants. Arrows in panels A and B illustrate the position of the transitional vertebra in wild-type and mutant animals, respectively. There is a rudimentary rib on the T13 vertebra (open arrowhead in B). Thoracic and sacral vertebral shapes are illustrated in panels C and D. The position of the costal facet, marked by arrows in C, denotes the transitional vertebra. Panel D illustrates the morphology of the sacral vertebrae. The transverse processes of the mutant S3* vertebra (bottom row) have an intermediate shape.
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Related In: Results  -  Collection

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Figure 4: Vertebral phenotypes in Hoxc10 mutants. Arrows in panels A and B illustrate the position of the transitional vertebra in wild-type and mutant animals, respectively. There is a rudimentary rib on the T13 vertebra (open arrowhead in B). Thoracic and sacral vertebral shapes are illustrated in panels C and D. The position of the costal facet, marked by arrows in C, denotes the transitional vertebra. Panel D illustrates the morphology of the sacral vertebrae. The transverse processes of the mutant S3* vertebra (bottom row) have an intermediate shape.
Mentions: The lack of a functional Hoxc10 homeobox causes several homeotic transformations in the axial skeleton (Table 1, Figures 3 and 4). Wild-type C57Bl/6 mice typically have 30 precaudal vertebrae, with the more caudal vertebrae organized in T13L6S4 pattern, with thirteen thoracic vertebrae, six lumbar vertebrae and four sacral vertebrae 10, 11. Eighty percent of the wild-type mice examined in this study exhibited this pattern, with the remainder of the animals showing some mild variation in the shape of the L1, L6, or S1 segments; these types of variations are within the range of normal (10. Hoxc10 mutant mice also have 30 precaudal vertebrae, but the patterning of the vertebral column is altered. Most Hoxc10 mutant mice (33 of 34 examined) show a partial to complete transformation of the thirteenth thoracic vertebrae, precaudal vertebra 20 (PC20) into a lumbar identity, typified by the reduction or complete loss of the thirteenth rib. By definition, thoracic vertebrae are those vertebrae with attached ribs; hence loss of the thirteenth rib suggests a posterior transformation of the most caudal thoracic vertebra into a lumbar identity. The most caudal lumbar vertebra (PC25) often undergoes a similar transformation into a sacral (S1) identity (Figures 3 and 4). The sacrum in wild-type animals is typically comprised of four vertebrae. The first two vertebrae, S1 and S2, have butterfly-shaped, fused transverse processes. The next two sacral vertebrae, S3 and S4, have transverse processes that are not fused, with S3 having butterfly-shaped transverse processes and S4 having club-shaped transverse processes similar to those seen on more caudal vertebrae (Figures 2 and 3). In Hoxc10 mutant animals, the fourth sacral vertebra (S3* in Figures 3 and 4) exhibits an intermediate shape between a normal S3 and S4, and there are usually five sacral-like vertebrae, three fused and two free. This suggests an anterior transformation of the first caudal vertebra into a sacral identity. This transformation restores the register of the vertebral column and thus there is no overall loss of precaudal vertebrae. In combination, these alterations produce a T12(T13/L1)L5S5 pattern in 94% of mutant mice. Heterozygous mice show several intermediate patterns, most commonly T13L5S5 (31.5%) or T12(T13/L1)L5S5 (38.9%), suggesting dosage compensation. The transitional vertebra, defined as the most anterior vertebra to show a lumbar rather than a thoracic articulation between the pre- and postzygapophyses [28 and references therein] is normally the tenth thoracic vertebra (T10), whereas in the homozygous Hoxc10 mutants the transition occurs at the ninth thoracic vertebra (T9) (Figure 4).

Bottom Line: We have identified patterning defects resulting from the targeted mutation of Hoxc10, a member of the Hox10 paralogous family.Our results also suggest a general role for Hoxc10 in regulating chondrogenesis and osteogenesis in the hindlimb, along with a specific role in shaping femoral architecture.These results suggest a role for Hoxc10 in generating or maintaining the normal complement of lumbar motor neurons.

View Article: PubMed Central - PubMed

Affiliation: Department of Psychiatry and Biobehavioral Science, UCLA School of Medicine, Los Angeles, CA 90095, USA.

ABSTRACT
Vertebrate Hox genes regulate many aspects of embryonic body plan development and patterning. In particular, Hox genes have been shown to regulate regional patterning of the axial and appendicular skeleton and of the central nervous system. We have identified patterning defects resulting from the targeted mutation of Hoxc10, a member of the Hox10 paralogous family. Hoxc10 mutant mice have skeletal transformations in thoracic, lumbar, and sacral vertebrae and in the pelvis, along with alterations in the bones and ligaments of the hindlimbs. These results suggest that Hoxc10, along with other members of the Hox10 paralogous gene family, regulates vertebral identity at the transition from thoracic to lumbar and lumbar to sacral regions. Our results also suggest a general role for Hoxc10 in regulating chondrogenesis and osteogenesis in the hindlimb, along with a specific role in shaping femoral architecture. In addition, mutant mice have a reduction in lumbar motor neurons and a change in locomotor behavior. These results suggest a role for Hoxc10 in generating or maintaining the normal complement of lumbar motor neurons.

Show MeSH
Related in: MedlinePlus