{\it Hox\/} genes and specification of regional identity in the axial skeleton: Analysis of the individual and combined mutant phenotypes of the paralogous group 4 murine {\it Hox\/} genes; {\it hoxa\/}-4, {\it hoxb\/}-4 and {\it hoxd\/}-4

The Hox gene products are transcription factors involved in specifying regional identity along the anteroposterior body axis. In Drosophila, where these genes are known as HOM-C (Homeotic-complex) genes and where they have been most extensively studied, they are expressed in restricted domains along the anteroposterior axis with different anterior limits. Genetic analysis of a large number of gain- and loss-of-function alleles of these genes has revealed that these genes are important in specifying segmental identity at their anterior limits of expression. Furthermore, there is a functional dominance of posterior genes over anterior genes, such that posterior genes can dominantly specify their developmental programs in spite of the expression of more anterior genes in the same segment. In the mouse, there are four clusters of HOM-C genes, called Hox genes. Thus, there may be up to four genes, called paralogs, that are more highly homologous to each other and to their Drosophila homolog than they are to the other mouse Hox genes. The single mutants for two paralogous genes, hoxa-4 and hoxd-4, presented in this dissertation, are similar to several other mouse Hox mutants in that they show partial, incompletely penetrant homeotic transformations of vertebrae at their anterior limit of expression. These mutants were then bred with hoxb-4 mutants (Ramirez-Solis, et al. 1993) to generate the three possible double mutant combinations as well as the triple mutant. The skeletal phenotypes of these group 4 Hox compound mutants displayed clear alterations in regional identity, such that a nearly complete transformation towards the morphology of the first cervical vertebra occurs. These results suggest a certain degree of functional redundancy among paralogous genes in specifying regional identity. Furthermore, there was a remarkable dose-dependent increase in the number of vertebrae transformed to a first cervical vertebra identity, including the second through the fifth cervical vertebrae in the triple mutant. Thus, these genes are required in a larger anteroposterior domain than is revealed by the single mutant phenotypes alone, such that multiple mutations in these genes result in transformations of vertebrae that are not at their anterior limit of expression. ^

Coordination of murine limb muscle, skeleton and connective tissue development by Lmx1b

The underlying genetic defects of a congenital disease Nail-Patella Syndrome are loss-of-function mutations in the LMX1B gene. Lmx1b encodes a LIM-homeodomain transcription factor that is expressed specifically in the dorsal limb bud mesenchyme. Gain- and loss-of-function experiments suggest that Lmx1b is both necessary and sufficient to specify dorsal limb patterning. However, how Lmx1b coordinates patterning of the dorsal tissues in the limb, including muscle, skeleton and connective tissues, remains unknown. One possibility is that each tissue specifies its own pattern cell-autonomously, i.e., Lmx1b is expressed in tissues in which it functions and different tissues do not communicate with each other. Another possibility is that tissues that express Lmx1b interact with adjacent tissues and provide patterning information thereby directing the development of tissues non-cell-autonomously. Previous results showed that Lmx1b is expressed in limb connective tissue and skeleton, but is not expressed in muscle tissue. Moreover, muscles and muscle connective tissue are closely associated during development. Therefore, we hypothesize that Lmx1b controls limb muscle dorsal-ventral (DV) patterning through muscle connective tissue, but regulates skeleton and tendon/ligament development cell-autonomously. ^ To test this hypothesis, we first examined when and where the limb dorsal-ventral asymmetry is established during development. Subsequently, conditional knockout and overexpression experiments were performed to delete or activate Lmx1b in different tissues within the limb. Our results show that deletion of Lmx1b from whole limb mesenchyme results in all dorsal tissues, including muscle, tendon/ligament and skeleton, transforming into ventral structures. Skeleton-specific knockout of Lmx1b led to the dorsal duplication of distal sesamoid and metacarpal bones, but did not affect the pattern formation of other tissues, suggesting that Lmx1b controls skeleton development cell-autonomously. In addition, this skeleton-specific pattern alteration only occurs in distal limb tissues, not proximal limb tissues, indicating different regulatory mechanisms operate along the limb proximal-distal axis. Moreover, skeleton-specific ectopic expression of Lmx1b reveals a complementary skeletal-specific dorsalized phenotype. This result supports a cell-autonomous role for Lmx1b in dorsal-ventral skeletal patterning. This study enriched our understanding of limb development, and the insights from this research may also be applicable for the development of other organs. ^

Health disparities between the United States mainland and Puerto Rico, Guam, and the United States Virgin Islands (United States territories)

Health disparities have been documented for the United States mainland. No literature was found comparing the mainland population to that of Puerto Rico, Guam, and the United States Virgin Islands (United States territories). Using Healthy Lifestyle Characteristics of non-smoking, maintaining a healthy weight, consuming fruits/vegetables daily, and exercising regularly, the health of the mainland was compared to United States territories. The research questions were: (1) Among the characteristics, what are similarities/differences between citizens of the mainland United States and territories?, (2) Among the characteristics, what are similarities/differences in how the territories compare to each other?, (3) Does the mainland and the territories meet Healthy People 2010 goals for these characteristics?, (4) Are perceptions of health concordant or discordant with the characteristics for mainlanders and Puerto Ricans? ^ Using 2007 data from Behavioral Risk Factor Surveillance System (BRFSS), frequency distributions were compared for the Healthy Lifestyle Characteristics for the mainland territories. Research found smoking rates on Guam were statistically greater than the mainland, Puerto Rico or the Virgin Islands. Healthy body mass index levels and physical activity rates were better on Guam compared to other locations. Puerto Rico had significantly more overweight and obese persons, lower fruit/vegetable consumption rates, and lower physical activity rates than the mainland, Guam and the Virgin Islands. Research found mainlanders reported statistically greater participation in regular physical activity than did Puerto Ricans and Virgin Islanders; there were significant differences in fruit/vegetable consumption rates compared to both. The research found no locations met all four of Healthy People 2010 goals. Compared to mainlanders, research showed Puerto Ricans perceive their health significantly worse.^ A better understanding is needed for how United States citizens (mainlanders and territory residents) view participation in healthy behaviors and how health is affected by participating or not in healthy behaviors. For the year examined, Healthy People 2010 goals were not achieved. This study demonstrates Puerto Ricans’ health, using the four characteristics, is significantly worse than residents in the other locations. Public health programs targeting Puerto Ricans are warranted. Finally, this study highlights the need for continued research on the relationships among the mainland and territories.^