Christian Lanctôt

Neuroendocrine dysplasia in mice lacking protein tyrosine phosphatase σ

Protein tyrosine phosphatase σ (PTP-σ, encoded by the Ptprs gene) is a member of the LAR subfamily of receptor-like protein tyrosine phosphatases that is highly expressed during mammalian embryonic development in the germinal cell layer lining the lateral ventricles of the developing brain, dorsal root ganglia, Rathkes pouch, olfactory epithelium, retina and developing lung and heart. On the basis of its expression and homology with the Drosophila melanogaster orthologues DPTP99 and DPTP100A (Refs 5,6), which have roles in the targeting of axonal growth cones, we hypothesized that PTP-σ may also have a modulating function in cell-cell interactions, as well as in axon guidance during mammalian embryogenesis. To investigate its function in vivo, we generated Ptprs-deficient mice. The resulting Ptprs-/- animals display retarded growth, increased neonatal mortality, hyposmia and hypofecundity. Anatomical and histological analyses showed a decrease in overall brain size with a severe depletion of luteinizing hormone-releasing hormone (LHRH)-immunoreactive cells in Ptprs-/- hypothalamus. Ptprs-/- mice have an enlarged intermediate pituitary lobe, but smaller anterior and posterior lobes. These results suggest that tyrosine phosphorylation-dependent signalling pathways regulated by PTP-σ influence the proliferation and/or adhesiveness of various cell types in the developing hypothalamo-pituitary axis.

The PTX family of homeodomain transcription factors during pituitary developments.

A subfamily of bicoid-related homeodomain factors was recently discovered through its involvement in transcription of pituitary-specific genes. We isolated the first member of this family, Ptxl (pituitary homeobox 1), through its DNA binding properties whereas a second related gene, Ptx2 (RIEG), was identified by positional cloning as the causative gene for Riegers syndrome. The mechanisms of Ptx action on its target genes as well as its putative roles during development are reviewed with particular emphasis on its role in pituitary function.

Pituitary Homeobox 1 (Ptx1) Is Differentially Expressed during Pituitary Development1

Pituitary homeobox 1 (Ptx1) is a homeodomain-containing transcription factor acting on transcription of all pituitary hormone genes. Its expression is first detected in the stomodeal ectoderm and is maintained in all derivatives of this structure, including Rathkes pouch. We now show that Ptx1 is expressed in all pituitary cells but that it is differentially expressed in different lineages at both the messenger RNA and protein levels. On day 12.5 of mouse embryonic development, cells expressing the highest levels of Ptx1 are restricted to the forming pars tuberalis, also called the rostral tip, a region where the first alpha-glycoprotein subunit-expressing cells appear. Coimmunolocalization studies reveal that alpha-glycoprotein subunit-positive cells express the highest levels of Ptx1 throughout development and in the adult gland. The quantitative differences in Ptx1 expression in pituitary cell lineages may relate to a role in cell proliferation, lineage commitment, and/or the control of organ development.

Human and murine PTX1/Ptx1 gene maps to the region for Treacher Collins syndrome.

Ptx1 belongs to an expanding family of bicoid- related vertebrate homeobox genes. These genes, like their Drosophila homolog, seem to play a role in the development of anterior structures and, in particular, the brain and facies. We report the chromosomal localization of mouse Ptxl, and the cloning, sequencing, and chromosomal localization of the human homolog PTX1 The putative encoded proteins share 100% homology in the homeodomain and are 88% and 97% conserved in the N- and C-termini respectively. Intron/exon boundaries are also conserved. Murine Ptx1 was localized, by interspecific backcrossing, to Chr 13 within 2.6 cM of Caml. The gene resides centrally on Chromosome (Chr) 13 in a region syntenic with human Chr 5q. Subsequent analysis by fluorescent in situ hybridization places the human gene, PTX1, on 5q31, a region associated with Treacher Collins Franceschetti Syndrome. Taken together with the craniofacial expression pattern of Ptx1 during early development, the localization of the gene in this chromosomal area is consistent with an involvement in Treacher Collins Franceschetti Syndrome.

Pitx1 in vivo Promoter Activity and Mechanisms of Positive Autoregulation

During early mouse embryogenesis, Pitx1 (pituitary homeobox 1), a member of the bicoid subgroup of paired homeobox-containing transcription factors, marks the stomodeum, oral ectoderm, pituitary and first branchial arch in the anterior part of the embryo and lateral plate mesoderm only in the posterior half of the embryo. We have now defined Pitx1 promoter fragments that mimic the anterior but not posterior expression of Pitx1 in transgenic mice. In addition, we show positive regulation of this promoter in transfection studies by three members of the Pitx1 family (Pitx1, Pitx1b, Pitx2), as well as by a related factor, Otx1. Pitx1 autoregulation depends on DNA-binding and trans-activation domains of Pitx1 and it may be responsible for establishment and/or maintenance of the Pitx1 expression domain.