Anthony Percival-SmithWestern Science

Molecular Mechanisms of Morphogenesis

The development of a multicellular organism from a single celled fertilized egg has long fascinated Biologists.  Over the past thirty years, the major molecular components that control development have been identified.  The interaction between these components has been well characterized, and nowhere better illustrated than the hierarchy of factors that establish the segmented body plan of the fruit fly, Drosophila melanogaster.  Many of these factors constitute the conserved genetic toolkit required for the development of all animal body plans.   We study one set of proteins that are part of this genetic toolkit: the HOX proteins. 

The HOX proteins we study are required for determining the number of segments that form, Fushi tarazu, and for determining the identity/structure that a segment will develop, Proboscipedia and Sex combs reduced.  The HOX proteins are transcription factors that regulate the expression of genes.  Although most transcription factors are thought to be composed of modular domains that mediate an unique aspect of transcription factor function like DNA binding, transcriptional activation/repression, and binding regulatory factors, the HOX proteins are proving to be quite dissimilar to this view of the archetypic transcription factor in being composed in most cases of small peptide motifs that make small and differential contributions to overall HOX activity.  We are interested in how HOX proteins work as transcription factors and what processes they control in developmental programs.

Hox genes

Sex combs reduced

SCR is required both for determination of first thoracic segment identity and labial (proboscis) identity.  Our present working hypothesis is SCR employs two activities to determine these identities and PB seems to act as a competence factor that aids the transformation of SCR from determining T1 identity to determining labial identity (Percival-Smith et al., 2013).   Determination of labial identity is not conserved in the murine SCR homolog HOXA5, and we are presently determining when during evolution does SCR acquire the activity to determine labial identity, that is, is labial determination insect, arthropod or protostome specific.

Model

Model for the role of PB in activating SCRlab activity during metamorphosis but not embryogenesis.

Phosphorylation of HOX proteins

HOX transcription factors are also phosphoproteins, and it has long been hypothesized that HOX activities are regulated by phosphorylation.  Many studies have indicated a role for phosphorylation in regulating HOX activity; however, some of these studies have not stood up to close scrutiny (Moazzen et al., 2009).  The study of HOX phosphorylation lacks an accurate map of all the phosphorylated residues.  This map would be the optimum starting point for the study of the regulation of HOX activity by phosphorylation.

Fushi tarazu

Fushi tarazu has been a long term focus of the lab.  It is a HOX protein that during evolution of insects has been become a pair-rule segmentation protein in Drosophila.  Twenty years ago FTZ was found to have a Homeodomain-independent activity (Fitzpatrick et al., 1992; Hyduk and Percival-Smith 1996).  We have been trying to determine the all the functional domains of FTZ since. 

Maxillary palp development

Proboscipedia is required for the determination of the maxillary palp when expressed alone and the proboscis when coexpressed with SCR.  For maxillary palp determination PB is expressed during the first 24 hours of metamorphosis in the maxillary palp.  We are using a combination of genetics and live imaging of metamorphosis to study the role of PB in maxillary palp development.