Thyroid hormone-regulated chromatin landscape and transcriptional sensitivity of the pituitary gland.

Thyroid hormone (3,5,3'-triiodothyronine, T3) is a key regulator of pituitary gland function. The response to T3 is thought to hinge crucially on interactions of nuclear T3 receptors with enhancers but these sites in pituitary chromatin remain surprisingly obscure. Here, we investigate genome-wide receptor binding in mice using tagged endogenous thyroid hormone receptor β (TRβ) and analyze T3-regulated open chromatin using an anterior pituitary-specific Cre driver (Thrb).

Targeted and selective knockout of the TLQP-21 neuropeptide unmasks its unique role in energy homeostasis.

Pro-peptide precursors are processed into biologically active peptide hormones or neurotransmitters, each playing an essential role in physiology and disease. Genetic loss of function of a pro-peptide precursor results in the simultaneous ablation of all biologically-active peptides within that precursor, often leading to a composite phenotype that can be difficult to align with the loss of specific peptide components. Due to this biological constraint and technical limitations, mice carrying the selective ablation of individual peptides encoded by pro-peptide precursor genes, while leaving the other peptides unaffected, have remained largely unaddressed.

Noncoding Mutations in a Thyroid Hormone Receptor Gene That Impair Cone Photoreceptor Function.

The function of a hormone receptor requires mechanisms to control precisely where, when, and at what level the receptor gene is expressed. An intriguing case concerns the selective induction of thyroid hormone receptor β2 (TRβ2), encoded by Thrb, in the pituitary and also in cone photoreceptors, in which it critically regulates expression of the opsin photopigments that mediate color vision. Here, we investigate the physiological significance of a candidate enhancer for induction of TRβ2 by mutagenesis of a conserved intron region in its natural context in the endogenous Thrb gene in mice.

Generation, characterization, and use of EKLF(Klf1)/CRE knock-in mice for cell-restricted analyses.

Introduction: EKLF/Klf1 is a tissue-restricted transcription factor that plays a critical role in all aspects of erythropoiesis. Of particular note is its tissue-restricted pattern of expression, a property that could prove useful for expression control of a linked marker or enzymatic gene.

Methods And Results: With this in mind, we fused the CRE recombinase to the genomic EKLF coding region and established mouse lines.

Role of VGF-derived carboxy-terminal peptides in energy balance and reproduction: analysis of "humanized" knockin mice expressing full-length or truncated VGF.

Targeted deletion of VGF, a secreted neuronal and endocrine peptide precursor, produces lean, hypermetabolic, and infertile mice that are resistant to diet-, lesion-, and genetically-induced obesity and diabetes. Previous studies suggest that VGF controls energy expenditure (EE), fat storage, and lipolysis, whereas VGF C-terminal peptides also regulate reproductive behavior and glucose homeostasis. To assess the functional equivalence of human VGF(1-615) (hVGF) and mouse VGF(1-617) (mVGF), and to elucidate the function of the VGF C-terminal region in the regulation of energy balance and susceptibility to obesity, we generated humanized VGF knockin mouse models expressing full-length hVGF or a C-terminally deleted human VGF(1-524) (hSNP), encoded by a single nucleotide polymorphism (rs35400704).

Interplay of host microbiota, genetic perturbations, and inflammation promotes local development of intestinal neoplasms in mice.

The preferential localization of some neoplasms, such as serrated polyps (SPs), in specific areas of the intestine suggests that nongenetic factors may be important for their development. To test this hypothesis, we took advantage of transgenic mice that expressed HB-EGF throughout the intestine but developed SPs only in the cecum. Here we show that a host-specific microbiome was associated with SPs and that alterations of the microbiota induced by antibiotic treatment or by embryo transfer rederivation markedly inhibited the formation of SPs in the cecum.

Protein tyrosine phosphatase PTPN14 is a regulator of lymphatic function and choanal development in humans.

The lymphatic vasculature is essential for the recirculation of extracellular fluid, fat absorption, and immune function and as a route of tumor metastasis. The dissection of molecular mechanisms underlying lymphangiogenesis has been accelerated by the identification of tissue-specific lymphatic endothelial markers and the study of congenital lymphedema syndromes. We report the results of genetic analyses of a kindred inheriting a unique autosomal-recessive lymphedema-choanal atresia syndrome.

Enhancement of IVF in the mouse by zona-drilling.

Cryopreservation of mouse sperm has become an essential method for the long-term storage of novel, genetically modified mouse lines. Cryopreserved sperm from most hybrid lines can be effectively used for in vitro fertilization (IVF) of mouse oocytes. Unfortunately, IVF recovery with cryopreserved sperm from inbred lines is very inefficient.

Transport of mouse lines by shipment of live embryos.

Advances in techniques for the genetic manipulation of the laboratory mouse have resulted in a vast array of novel mouse lines for research. One challenge facing researchers is the ability to rapidly share genetically modified mouse lines with collaborators at other institutions. The standard method of shipping live animals has its share of problems, including the acceptability of the mice at the receiving institution based on health status, as well as the length of time that mice are maintained in quarantine at the receiving institution.

Transgenic neuronal expression of proopiomelanocortin attenuates hyperphagic response to fasting and reverses metabolic impairments in leptin-deficient obese mice.

Hypothalamic proopiomelanocortin (POMC) gene expression is reduced in many forms of obesity and diabetes, particularly in those attributable to deficiencies in leptin or its receptor. To assess the functional significance of POMC in mediating metabolic phenotypes associated with leptin deficiency, leptin-deficient mice bearing a transgene expressing the POMC gene under control of the neuron-specific enolase promoter were produced. The POMC transgene attenuated fasting-induced hyperphagia in wild-type mice.

Gcm1 expression defines three stages of chorio-allantoic interaction during placental development.

The formation of the labyrinth layer is a critical step of placental development. The transcription factor glial cells missing 1 (Gcm1) plays a pivotal role in labyrinth development, but the sequence of events controlling its expression has not been identified yet. Our studies presented herein show that Gcm1 expression occurs in three distinct phases during placental development, each specific to a particular stage of chorio-allantois interaction.