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Yeha Kim, Soyeon Lim, Taejeong Ha, You-Hyang Song, Young-In Sohn, Dae-Jin Park, Sun-Sook Paik, Joo-Ri Kim-Kaneyama, Mi-Ryoung Song, Amanda Leung, Edward M Levine, In-Beom Kim, Yong Sook Goo, Seung-Hee Lee, Kyung Hwa Kang, Jin Woo Kim
The visual responses of vertebrates are sensitive to the overall composition of retinal interneurons including amacrine cells, which tune the activity of the retinal circuitry. The expression of Paired-homeobox 6 (PAX6) is regulated by multiple cis-DNA elements including the intronic α-enhancer, which is active in GABAergic amacrine cell subsets. Here, we report that the transforming growth factor ß1-induced transcript 1 protein (Tgfb1i1) interacts with the LIM domain transcription factors Lhx3 and Isl1 to inhibit the α-enhancer in the post-natal mouse retina...
January 31, 2017: ELife
Peng Chen, Paolo Piaggi, Michael Traurig, Clifton Bogardus, William C Knowler, Leslie J Baier, Robert L Hanson
AIMS/HYPOTHESIS: Individuals exposed to maternal diabetes in utero are more likely to develop metabolic and cardiovascular diseases later in life. This may be partially attributable to epigenetic regulation of gene expression. We performed an epigenome-wide association study to examine whether differential DNA methylation, a major source of epigenetic regulation, can be observed in offspring of mothers with type 2 diabetes during the pregnancy (OMD) compared with offspring of mothers with no diabetes during the pregnancy (OMND)...
January 26, 2017: Diabetologia
Natascia Di Iorgi, Giovanni Morana, Anna Elsa Maria Allegri, Flavia Napoli, Roberto Gastaldi, Annalisa Calcagno, Giuseppa Patti, Sandro Loche, Mohamad Maghnie
Growth hormone deficiency (GHD) may result from a failure of hypothalamic GHRH production or release, from congenital disorders of pituitary development, or from central nervous system insults including tumors, surgery, trauma, radiation or infiltration from inflammatory diseases. Idiopathic, isolated GHD is the most common sporadic form of hypopituitarism. GHD may also occur in combination with other pituitary hormone deficiencies, and is often referred to as hypopituitarism, combined pituitary hormone deficiency (CPHD), multiple pituitary hormone deficiency (MPHD) or panhypopituitarism...
December 2016: Best Practice & Research. Clinical Endocrinology & Metabolism
Mara Giordano
Research over the last 20 years has led to the elucidation of the genetic aetiologies of Isolated Growth Hormone Deficiency (IGHD) and Combined Pituitary Hormone Deficiency (CPHD). The pituitary plays a central role in growth regulation, coordinating the multitude of central and peripheral signals to maintain the body's internal balance. Naturally occurring mutation in humans and in mice have demonstrated a role for several factors in the aetiology of IGHD/CPHD. Mutations in the GH1 and GHRHR genes shed light on the phenotype and pathogenesis of IGHD whereas mutations in transcription factors such as HESX1, PROP1, POU1F1, LHX3, LHX4, GLI2 and SOX3 contributed to the understanding of CPHD...
December 2016: Best Practice & Research. Clinical Endocrinology & Metabolism
Ho Sung Rhee, Michael Closser, Yuchun Guo, Elizaveta V Bashkirova, G Christopher Tan, David K Gifford, Hynek Wichterle
Generic spinal motor neuron identity is established by cooperative binding of programming transcription factors (TFs), Isl1 and Lhx3, to motor-neuron-specific enhancers. How expression of effector genes is maintained following downregulation of programming TFs in maturing neurons remains unknown. High-resolution exonuclease (ChIP-exo) mapping revealed that the majority of enhancers established by programming TFs are rapidly deactivated following Lhx3 downregulation in stem-cell-derived hypaxial motor neurons...
December 21, 2016: Neuron
Silvia Velasco, Mahmoud M Ibrahim, Akshay Kakumanu, Görkem Garipler, Begüm Aydin, Mohamed Ahmed Al-Sayegh, Antje Hirsekorn, Farah Abdul-Rahman, Rahul Satija, Uwe Ohler, Shaun Mahony, Esteban O Mazzoni
Direct cell programming via overexpression of transcription factors (TFs) aims to control cell fate with the degree of precision needed for clinical applications. However, the regulatory steps involved in successful terminal cell fate programming remain obscure. We have investigated the underlying mechanisms by looking at gene expression, chromatin states, and TF binding during the uniquely efficient Ngn2, Isl1, and Lhx3 motor neuron programming pathway. Our analysis reveals a highly dynamic process in which Ngn2 and the Isl1/Lhx3 pair initially engage distinct regulatory regions...
February 2, 2017: Cell Stem Cell
C-Z Wang, L-L Guo, B-Y Han, X Su, Q-H Guo, Y-M Mu
Pituitary stalk interruption syndrome (PSIS) is a rare congenital defect manifesting with varying degrees of pituitary hormone deficiency. The signs and symptoms of PSIS during the neonatal period and infancy are often overlooked and therefore diagnosis is delayed. The typical manifestations of PSIS can be detected by magnetic resonance imaging. Several genes in the Wnt, Notch and Shh signalling pathways related to hypothalamic-pituitary development, such as PIT1, PROP1, LHX3/LHX4, PROKR2, OTX2, TGIF and HESX1, have been found to be associated with PSIS...
January 2017: Journal of Neuroendocrinology
Enzo Cohen, Mohamad Maghnie, Nathalie Collot, Juliane Leger, Florence Dastot, Michel Polak, Sophie Rose, Philippe Touraine, Philippe Duquesnoy, Maïté Tauber, Bruno Copin, Anne-Marie Bertrand, Frederic Brioude, Daniela Larizza, Thomas Edouard, Laura González Briceño, Irène Netchine, Isabelle Oliver-Petit, Marie-Laure Sobrier, Serge Amselem, Marie Legendre
CONTEXT: LHX4 encodes a LIM-homeodomain transcription factor implicated in early pituitary development. In humans, only 13 heterozygous LHX4 mutations have been associated with congenital hypopituitarism. OBJECTIVE: To evaluate the prevalence of LHX4 mutations in patients with hypopituitarism, and to precise the associated phenotypes. To characterize the functional impact of the identified variants and the respective role of the two LIM domains of LHX4. PATIENTS AND DESIGN: We screened 417 unrelated patients with isolated growth hormone deficiency or combined pituitary hormone deficiency associated with ectopic posterior pituitary and/or sella turcica anomalies for LHX4 mutations (Sanger sequencing)...
November 7, 2016: Journal of Clinical Endocrinology and Metabolism
Kyung-Tai Kim, Namhee Kim, Hwan-Ki Kim, Hojae Lee, Hannah N Gruner, Peter Gergics, Chungoo Park, Grant S Mastick, Hae-Chul Park, Mi-Ryoung Song
LIM-homeodomain (HD) transcription factors form a multimeric complex and assign neuronal subtype identities, as demonstrated by the hexameric ISL1-LHX3 complex which gives rise to somatic motor (SM) neurons. However, the roles of combinatorial LIM code in motor neuron diversification and their subsequent differentiation is much less well understood. In the present study, we demonstrate that the ISL1 controls postmitotic cranial branchiomotor (BM) neurons including the positioning of the cell bodies and peripheral axon pathfinding...
November 7, 2016: Scientific Reports
Masatsugu Masuda, Yan Li, Kwang Pak, Eduardo Chavez, Lina Mullen, Allen F Ryan
Few enhancers that target gene expression to inner ear hair cells (HCs) have been identified. Using transgenic analysis of enhanced green fluorescent protein (eGFP) reporter constructs and bioinformatics, we evaluated the control of pou4f3 gene expression, since it is expressed only in HCs within the inner ear and continues to be expressed throughout life. An 8.5-kb genomic DNA fragment 5' to the start codon, containing three regions of high cross-species homology, drove expression in all embryonic and neonatal HCs, and adult vestibular and inner HCs, but not adult outer HCs...
September 3, 2016: Molecular Neurobiology
Julia Rohayem, Hendrik Drechsel, Bettina Tittel, Gabriele Hahn, Roland Pfaeffle, Angela Huebner
BACKGROUND: Growth hormone (GH) has been used to treat children with GH deficiency (GHD) since 1966. AIMS: Using a combined retrospective and cross-sectional approach, we explored the long-term outcomes of patients with GHD, analysed factors influencing therapeutic response, determined persistence into adulthood, investigated pituitary morphology, and screened for mutations in causative genes. METHODS: The files of 96 GH-deficient children were reviewed...
2016: Hormone Research in Pædiatrics
Yoanne M Clovis, So Yeon Seo, Ji-Sun Kwon, Jennifer C Rhee, Sujeong Yeo, Jae W Lee, Seunghee Lee, Soo-Kyung Lee
During development, two cell types born from closely related progenitor pools often express identical transcriptional regulators despite their completely distinct characteristics. This phenomenon implies the need for a mechanism that operates to segregate the identities of the two cell types throughout differentiation after initial fate commitment. To understand this mechanism, we investigated the fate specification of spinal V2a interneurons, which share important developmental genes with motor neurons (MNs)...
August 9, 2016: Cell Reports
Jean-Noël Laverrière, David L'Hôte, Laure Tabouy, Anne-Laure Schang, Bruno Quérat, Joëlle Cohen-Tannoudji
Gonadotrope cell identity genes emerge in a stepwise process during mouse pituitary development. Cga, encoding for the α-subunit of TSH, LH, and FSH, is initially detected at E11.5 followed by Gnrhr and steroidogenic factor Sf1 at E13.5, specifying cells engaged in a gonadotrope cell fate. Lhb and Fshb appear at E16.5 and 17.5, respectively, typifying differentiated gonadotrope cells. Using the αT1-1, αT3-1 and LβT2 cell lines recapitulating these stages of gonadotrope differentiation, DNA methylation at Gnrhr and Sf1 was investigated...
October 15, 2016: Molecular and Cellular Endocrinology
Hitoshi Kodama, Yoshimasa Miyata, Mami Kuwajima, Ryoichi Izuchi, Ayumi Kobayashi, Fuki Gyoja, Takeshi A Onuma, Gaku Kumano, Hiroki Nishida
During embryonic induction, the responding cells invoke an induced developmental program, whereas in the absence of an inducing signal, they assume a default uninduced cell fate. Suppression of the default fate during the inductive event is crucial for choice of the binary cell fate. In contrast to the mechanisms that promote an induced cell fate, those that suppress the default fate have been overlooked. Upon induction, intracellular signal transduction results in activation of genes encoding key transcription factors for induced tissue differentiation...
August 1, 2016: Developmental Biology
Heejin Nam, Seunghee Lee
During spinal cord development, motor neuron (MN) axons exit the spinal cord ventrally, although the molecular basis for this process remains poorly understood. STAM1 and HRS form a complex involved with endosomal targeting of cargo proteins, including the chemokine receptor CXCR4. Interestingly, the absence of CXCR4 signaling in spinal MNs is known to result in improper extension of the axons into the dorsal side of the spinal cord. Here, we report that the MN-specific ISL1-LHX3 complex directly transactivates the Stam1 gene and that STAM1 functions in determining the ventral spinal MN axonal projections...
July 1, 2016: Development
Hadar Haim-Pinhas, Rivka Kauli, Pearl Lilos, Zvi Laron
OBJECTIVE: Congenital MPHD is a rare condition caused by mutations in pituitary transcription factors genes: PROP1, POU1F1 (PIT1), HESX1, LHX3, LHX4. DESIGN: We evaluated in a retrospective study the effects on growth and development in 29 patients with congenital MPHD (cMPHD), during hGH replacement therapy alone and combined with sex hormones. Twenty nine patients with cMPHD were included and diagnosed, treated and followed in our clinic from diagnosis to adult age...
April 2016: Growth Hormone & IGF Research
Saishu Yoshida, Takako Kato, Naoto Nishimura, Naoko Kanno, Mo Chen, Hiroki Ueharu, Hiroto Nishihara, Yukio Kato
The LIM-homeobox transcription factors LHX2 and LHX3s (LHX3a and LHX3b) are thought to be involved in regulating the pituitary glycoprotein hormone subunit genes Cga and Fshβ. These two factors show considerable differences in their amino acid sequences for DNA binding and protein-protein interactions and in their vital function in pituitary development. Hence, we compared the DNA binding properties and transcriptional activities of Cga and Fshβ between LHX2 and LHX3s. A gel mobility shift assay for approximately 1...
June 17, 2016: Journal of Reproduction and Development
Nisha R Iyer, James E Huettner, Jessica C Butts, Chelsea R Brown, Shelly E Sakiyama-Elbert
Challenges in parsing specific contributions to spinal microcircuit architecture have limited our ability to model and manipulate those networks for improved functional regeneration after injury or disease. While spinal interneurons (INs) have been implicated in driving coordinated locomotor behaviors, they constitute only a small percentage of the spinal cord and are difficult to isolate from primary tissue. In this study, we employed a genetic strategy to obtain large quantities of highly enriched mouse embryonic stem cell (ESC)-derived V2a INs, an excitatory glutamatergic IN population that is defined by expression of the homeodomain protein Chx10 during development...
March 2016: Experimental Neurology
María Soler Artigas, Louise V Wain, Suzanne Miller, Abdul Kader Kheirallah, Jennifer E Huffman, Ioanna Ntalla, Nick Shrine, Ma'en Obeidat, Holly Trochet, Wendy L McArdle, Alexessander Couto Alves, Jennie Hui, Jing Hua Zhao, Peter K Joshi, Alexander Teumer, Eva Albrecht, Medea Imboden, Rajesh Rawal, Lorna M Lopez, Jonathan Marten, Stefan Enroth, Ida Surakka, Ozren Polasek, Leo-Pekka Lyytikäinen, Raquel Granell, Pirro G Hysi, Claudia Flexeder, Anubha Mahajan, John Beilby, Yohan Bossé, Corry-Anke Brandsma, Harry Campbell, Christian Gieger, Sven Gläser, Juan R González, Harald Grallert, Chris J Hammond, Sarah E Harris, Anna-Liisa Hartikainen, Markku Heliövaara, John Henderson, Lynne Hocking, Momoko Horikoshi, Nina Hutri-Kähönen, Erik Ingelsson, Åsa Johansson, John P Kemp, Ivana Kolcic, Ashish Kumar, Lars Lind, Erik Melén, Arthur W Musk, Pau Navarro, David C Nickle, Sandosh Padmanabhan, Olli T Raitakari, Janina S Ried, Samuli Ripatti, Holger Schulz, Robert A Scott, Don D Sin, John M Starr, Ana Viñuela, Henry Völzke, Sarah H Wild, Alan F Wright, Tatijana Zemunik, Deborah L Jarvis, Tim D Spector, David M Evans, Terho Lehtimäki, Veronique Vitart, Mika Kähönen, Ulf Gyllensten, Igor Rudan, Ian J Deary, Stefan Karrasch, Nicole M Probst-Hensch, Joachim Heinrich, Beate Stubbe, James F Wilson, Nicholas J Wareham, Alan L James, Andrew P Morris, Marjo-Riitta Jarvelin, Caroline Hayward, Ian Sayers, David P Strachan, Ian P Hall, Martin D Tobin
Lung function measures are used in the diagnosis of chronic obstructive pulmonary disease. In 38,199 European ancestry individuals, we studied genome-wide association of forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC) and FEV1/FVC with 1000 Genomes Project (phase 1)-imputed genotypes and followed up top associations in 54,550 Europeans. We identify 14 novel loci (P<5 × 10(-8)) in or near ENSA, RNU5F-1, KCNS3, AK097794, ASTN2, LHX3, CCDC91, TBX3, TRIP11, RIN3, TEKT5, LTBP4, MN1 and AP1S2, and two novel signals at known loci NPNT and GPR126, providing a basis for new understanding of the genetic determinants of these traits and pulmonary diseases in which they are altered...
December 4, 2015: Nature Communications
K Ziemnicka, B Budny, K Drobnik, D Baszko-Błaszyk, M Stajgis, K Katulska, R Waśko, E Wrotkowska, R Słomski, M Ruchała
The role of genetic background in childhood-onset combined pituitary hormone deficiency (CPHD) has been extensively studied. The major contributors are the PROP1, POU1F1, LHX3, LHX4 and HESX1 genes coding transcription factors implicated in pituitary organogenesis. The clinical consequences of mutations encompass impaired synthesis of a growth hormone (GH) and one or more concurrent pituitary hormones (i.e. LH, FSH, TSH, PRL). Manifestation of the disorder may vary due to various mutation impacts on the final gene products or an influence of environmental factors during pituitary organogenesis...
August 2016: Journal of Applied Genetics
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