ABSTRACT
The thyroid-stimulating hormone/thyrotropin (TSH) is the most relevant hormone in the control of thyroid gland physiology in adulthood. TSH effects on the thyroid gland are mediated by the interaction with a specific TSH receptor (TSHR). We studied the role of TSHTSHR signaling on gland morphogenesis and differentiation in the mouse embryo using mouse lines deprived either of TSH (pit(dw)pit(dw)) or of a functional TSHR (tshr(hyt)tshr(hyt) and TSHR-knockout lines). The results reported here show that in the absence of either TSH or a functional TSHR, the thyroid gland develops to a normal size, whereas the expression of thyroperoxidase and the sodium/iodide symporter are reduced greatly. Conversely, no relevant changes are detected in the amounts of thyroglobulin and the thyroid-enriched transcription factors TTF-1, TTF-2, and Pax8. These data suggest that the major role of the TSH/TSHR pathway is in controlling genes involved in iodide metabolism such as sodium/iodide symporter and thyroperoxidase. Furthermore, our data indicate that in embryonic life TSH does not play an equivalent role in controlling gland growth as in the adult thyroid.
Subject(s)
Gene Expression Regulation, Developmental/physiology , Receptors, Thyrotropin/physiology , Signal Transduction/physiology , Thyroid Gland/embryology , Thyrotropin/physiology , Animals , Antigens, Differentiation/biosynthesis , Antigens, Differentiation/genetics , Cell Differentiation , Crosses, Genetic , DNA-Binding Proteins/biosynthesis , DNA-Binding Proteins/genetics , Forkhead Transcription Factors , Gestational Age , Humans , Hypothyroidism/embryology , Hypothyroidism/genetics , Iodide Peroxidase/biosynthesis , Iodide Peroxidase/genetics , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Mice, Knockout , Morphogenesis , Nuclear Proteins/biosynthesis , Nuclear Proteins/genetics , Organ Size , PAX8 Transcription Factor , Paired Box Transcription Factors , RNA, Messenger/biosynthesis , RNA, Messenger/genetics , Receptors, Thyrotropin/deficiency , Receptors, Thyrotropin/genetics , Recombinant Fusion Proteins/physiology , Repressor Proteins/biosynthesis , Repressor Proteins/genetics , Symporters/biosynthesis , Symporters/genetics , Thyroglobulin/biosynthesis , Thyroglobulin/genetics , Thyroid Gland/growth & development , Thyroid Gland/pathology , Thyroid Nuclear Factor 1 , Thyrotropin/deficiency , Thyrotropin/genetics , Trans-Activators/biosynthesis , Trans-Activators/genetics , Transcription Factors/biosynthesis , Transcription Factors/geneticsABSTRACT
Over the last ten years, many genes involved in the induction, specification and regionalization of the brain have been identified and characterized at the functional level through a series of animal models. Among these genes, both Otx1 and Otx2, two murine homologues of the Drosophila orthodenticle (otd) gene which encode transcription factors, play a pivotal role in the morphogenesis of the rostral brain. Classical knock-out studies have revealed that Otx2 is fundamental for the early specification and subsequent maintenance of the anterior neural plate, whereas Otx1 is mainly necessary for both normal corticogenesis and sense organ development. A minimal threshold of both gene products is required for correct patterning of the fore-midbrain and positioning of the isthmic organizer. A third gene, Orthopedia (Otp) is a key element of the genetic pathway controlling development of the neuroendocrine hypothalamus. This review deals with a comprehensive analysis of the Otx1, Otx2 and Otp functions, and with the possible evolutionary implications suggested by the models in which the Otx genes are reciprocally replaced or substituted by the Drosophila homologue, otd.
Subject(s)
Brain/embryology , Brain/metabolism , Drosophila Proteins , Homeodomain Proteins , Nerve Tissue Proteins/biosynthesis , Nerve Tissue Proteins/physiology , Trans-Activators/biosynthesis , Trans-Activators/physiology , Animals , Basic Helix-Loop-Helix Transcription Factors , Central Nervous System/embryology , Drosophila/embryology , Mice , Mice, Knockout , Mice, Mutant Strains , Models, Genetic , Otx Transcription Factors , POU Domain Factors , Phenotype , Repressor Proteins/biosynthesis , Repressor Proteins/physiology , Sense Organs/embryology , Transcription Factors/biosynthesisABSTRACT
Development of the neuroendocrine hypothalamus is characterized by a precise series of morphogenetic milestones culminating in terminal differentiation of neurosecretory cell lineages. The homeobox-containing gene Orthopedia (Otp) is expressed in neurons giving rise to the paraventricular (PVN), supraoptic (SON), anterior periventricular (aPV), and arcuate (ARN) nuclei throughout their development. Homozygous Otp(-/-) mice die soon after birth and display progressive impairment of crucial neuroendocrine developmental events such as reduced cell proliferation, abnormal cell migration, and failure in terminal differentiation of the parvocellular and magnocellular neurons of the aPV, PVN, SON, and ARN. Moreover, our data provide evidence that Otp and Sim1, a bHLH-PAS transcription factor that directs terminal differentiation of the PVN, SON, and aPV, act in parallel and are both required to maintain Brn2 expression which, in turn, is required for neuronal cell lineages secreting oxytocin (OT), arginine vasopressin (AVP), and corticotropin-releasing hormone (CRH).
Subject(s)
Cell Lineage/genetics , Homeodomain Proteins/physiology , Hypothalamus/embryology , Nerve Tissue Proteins/physiology , Animals , Apoptosis , Body Patterning , Cell Division , Female , Gene Deletion , HeLa Cells , Homeodomain Proteins/genetics , Humans , Hypothalamus/cytology , Male , Mice , Mice, Inbred C57BL , Mice, Mutant Strains , Nerve Tissue Proteins/geneticsABSTRACT
The Dlx5 gene encodes a Distal-less-related DNA-binding homeobox protein first expressed during early embryonic development in anterior regions of the mouse embryo. In later developmental stages, it appears in the branchial arches, the otic and olfactory placodes and their derivatives, in restricted brain regions, in all extending appendages and in all developing bones. We have created a null allele of the mouse Dlx5 gene by replacing exons I and II with the E. coli lacZ gene. Heterozygous mice appear normal. Beta-galactosidase activity in Dlx5+/- embryos and newborn animals reproduces the known pattern of expression of the gene. Homozygous mutants die shortly after birth with a swollen abdomen. They present a complex phenotype characterised by craniofacial abnormalities affecting derivatives of the first four branchial arches, severe malformations of the vestibular organ, a delayed ossification of the roof of the skull and abnormal osteogenesis. No obvious defect was observed in the patterning of limbs and other appendages. The defects observed in Dlx5-/- mutant animals suggest multiple and independent roles of this gene in the patterning of the branchial arches, in the morphogenesis of the vestibular organ and in osteoblast differentiation.
Subject(s)
Bone and Bones/abnormalities , Craniofacial Abnormalities/genetics , Genes, Homeobox , Homeodomain Proteins/genetics , Vestibule, Labyrinth/abnormalities , Animals , Animals, Newborn , Apoptosis/genetics , Base Sequence , Brain/abnormalities , Cell Differentiation/genetics , Cell Division/genetics , DNA Primers/genetics , Gene Expression Regulation, Developmental , Gene Targeting , In Situ Hybridization , Lac Operon , Mice , Mice, Knockout , Mutation , Osteoblasts/cytology , PhenotypeABSTRACT
The Otx1 and Otx2 genes are two murine orthologues of the Orthodenticle (Otd) gene in Drosophila. In the developing mouse embryo, both Otx genes are expressed in the rostral head region and in certain sense organs such as the inner ear. Previous studies have shown that mice lacking Otx1 display abnormal patterning of the brain, whereas embryos lacking Otx2 develop without heads. In this study, we examined, at different developmental stages, the inner ears of mice lacking both Otx1 and Otx2 genes. In wild-type inner ears, Otx1, but not Otx2, was expressed in the lateral canal and ampulla, as well as part of the utricle. Ventral to the mid-level of the presumptive utricle, Otx1 and Otx2 were co-expressed, in regions such as the saccule and cochlea. Paint-filled membranous labyrinths of Otx1-/- mutants showed an absence of the lateral semicircular canal, lateral ampulla, utriculosaccular duct and cochleosaccular duct, and a poorly defined hook (the proximal part) of the cochlea. Defects in the shape of the saccule and cochlea were variable in Otx1-/- mice and were much more severe in an Otx1-/-;Otx2(+/)- background. Histological and in situ hybridization experiments of both Otx1-/- and Otx1-/-;Otx2(+/)- mutants revealed that the lateral crista was absent. In addition, the maculae of the utricle and saccule were partially fused. In mutant mice in which both copies of the Otx1 gene were replaced with a human Otx2 cDNA (hOtx2(1)/ hOtx2(1)), most of the defects associated with Otx1-/- mutants were rescued. However, within the inner ear, hOtx2 expression failed to rescue the lateral canal and ampulla phenotypes, and only variable rescues were observed in regions where both Otx1 and Otx2 are normally expressed. These results suggest that both Otx genes play important and differing roles in the morphogenesis of the mouse inner ear and the development of its sensory organs.
