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1.
Dev Dyn ; 244(2): 122-33, 2015 Feb.
Article in English | MEDLINE | ID: mdl-25382630

ABSTRACT

BACKGROUND: Cleft palate occurs in up to 1:1,000 live births and is associated with mutations in multiple genes. Palatogenesis involves a complex choreography of palatal shelf elongation, elevation, and fusion. Transforming growth factor ß (TGFß) and bone morphogenetic protein 2 (BMP2) canonical signaling is required during each stage of palate development. The type III TGFß receptor (TGFßR3) binds all three TGFß ligands and BMP2, but its contribution to palatogenesis is unknown. RESULTS: The role of TGFßR3 during palate formation was found to be during palatal shelf elongation and elevation. Tgfbr3(-) (/) (-) embryos displayed reduced palatal shelf width and height, changes in proliferation and apoptosis, and reduced vascular and osteoblast differentiation. Abnormal vascular plexus organization as well as aberrant expression of arterial (Notch1, Alk1), venous (EphB4), and lymphatic (Lyve1) markers was also observed. Decreased osteoblast differentiation factors (Runx2, alk phos, osteocalcin, col1A1, and col1A2) demonstrated poor mesenchymal cell commitment to the osteoblast lineage within the maxilla and palatal shelves in Tgfbr3(-) (/) (-) embryos. Additionally, in vitro bone mineralization induced by osteogenic medium (OM+BMP2) was insufficient in Tgfbr3(-) (/) (-) palatal mesenchyme, but mineralization was rescued by overexpression of TGFßR3. CONCLUSIONS: These data reveal a critical, previously unrecognized role for TGFßR3 in vascular and osteoblast development during palatogenesis.


Subject(s)
Calcification, Physiologic/physiology , Gene Expression Regulation, Developmental/physiology , Neovascularization, Physiologic/physiology , Organogenesis/physiology , Osteoblasts/metabolism , Proteoglycans/metabolism , Receptors, Transforming Growth Factor beta/metabolism , Animals , Antigens, Differentiation/biosynthesis , Mesoderm/cytology , Mesoderm/embryology , Mice , Mice, Knockout , Osteoblasts/cytology , Palate, Hard/blood supply , Palate, Hard/cytology , Palate, Hard/embryology , Proteoglycans/genetics , Receptors, Transforming Growth Factor beta/genetics
2.
Endocrinology ; 151(8): 3836-46, 2010 Aug.
Article in English | MEDLINE | ID: mdl-20519368

ABSTRACT

Recent data have demonstrated that mutations in the receptor for neurokinin B (NKB), the NK-3 receptor (NK3R), produce hypogonadotropic hypogonadism in humans. These data, together with reports that NKB expression increases after ovariectomy and in postmenopausal women, have led to the hypothesis that this tachykinin is an important stimulator of GnRH secretion. However, the NK3R agonist, senktide, inhibited LH secretion in rats and mice. In this study, we report that senktide stimulates LH secretion in ewes. A dramatic increase in LH concentrations to levels close to those observed during the preovulatory LH surge was observed after injection of 1 nmol senktide into the third ventricle during the follicular, but not in the luteal, phase. Similar increases in LH secretion occurred after insertion of microimplants containing this agonist into the retrochiasmatic area (RCh) in anestrous or follicular phase ewes. A low-dose microinjection (3 pmol) of senktide into the RCh produced a smaller but significant increase in LH concentrations in anestrous ewes. Moreover, NK3R immunoreactivity was clearly evident in the RCh, although it was not found in A15 dopaminergic cell bodies in this region. These data provide evidence that NKB stimulates LH (and presumably GnRH) secretion in ewes and point to the RCh as one important site of action. Based on these data, and the effects of NK3R mutations in humans, we hypothesize that NKB plays an important stimulatory role in the control of GnRH and LH secretion in nonrodent species.


Subject(s)
Brain/drug effects , Luteinizing Hormone/metabolism , Neurokinin B/pharmacology , Receptors, Neurokinin-3/physiology , Anestrus/blood , Anestrus/drug effects , Animals , Brain/metabolism , Dopamine/metabolism , Female , Follicular Phase/drug effects , Follicular Phase/metabolism , Follicular Phase/physiology , Gonadotropin-Releasing Hormone/blood , Gonadotropin-Releasing Hormone/metabolism , Injections, Intraventricular , Luteal Phase/drug effects , Luteal Phase/metabolism , Luteal Phase/physiology , Luteinizing Hormone/blood , Models, Biological , Neurokinin B/physiology , Neurons/drug effects , Neurons/metabolism , Neurotransmitter Agents/pharmacology , Peptide Fragments/administration & dosage , Peptide Fragments/pharmacology , Receptors, Neurokinin-3/agonists , Receptors, Neurokinin-3/metabolism , Sheep , Substance P/administration & dosage , Substance P/analogs & derivatives , Substance P/pharmacology
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