Arcuate nucleus expression of NKX2.1 and DLX and lineages expressing these transcription factors in neuropeptide Y+, proopiomelanocortin+, and tyrosine hydroxylase+ neurons in neonatal and adult mice

Despite its small size, the arcuate nucleus of the hypothalamus has a critical role in regulating energy homeostasis. We have begun to define genetic approaches to express genes in specific cell types within the developing arcuate nucleus, to allow precise molecular perturbations of these cells. Furthermore, our analysis aims to contribute to defining the transcriptional networks that regulate the development of function of the arcuate neurons. Here, we define the neuronal cells types within the arcuate that express Nkx2.1 and Dlx homeobox genes. In addition, we used mice expressing Cre recombinase from the Dlx5/6 intergenic enhancer (Dlx5/6i) and from the Nkx2.1 locus to follow the fate of embryonic cells expressing these genes within the arcuate nucleus. We demonstrate that NKX2.1+ cells and their lineages are broadly expressed in arcuate neurons [γ‐aminobutyric acid (GABA)+, neuropeptide Y (NPY)+, proopiomelanocortin (POMC)+, tyrosine hydroxylase (TH)+] and glia (tanycytes). On the other hand, DLX+ cells and their lineages mark only GABA+ and TH+ (dopaminergic) neurons, and Dlx1–/– mutants have fewer TH+ neurons. These results have implications for the genetic control of arcuate development and function and for the utility of the Nkx2.1‐Cre and Dlx5/6i‐Cre mouse lines to alter gene expression in the developing arcuate. J. Comp. Neurol. 517:37–50, 2009. © 2009 Wiley‐Liss, Inc.

[1]  J. Rubenstein,et al.  Distinct molecular pathways for development of telencephalic interneuron subtypes revealed through analysis of Lhx6 mutants , 2008, The Journal of comparative neurology.

[2]  R. Northcutt,et al.  Conserved pattern of OTP-positive cells in the paraventricular nucleus and other hypothalamic sites of tetrapods , 2008, Brain Research Bulletin.

[3]  S. Anderson,et al.  Fate mapping Nkx2.1‐lineage cells in the mouse telencephalon , 2008, The Journal of comparative neurology.

[4]  T. Iwanaga,et al.  Dmbx1 is essential in agouti-related protein action , 2007, Proceedings of the National Academy of Sciences.

[5]  J. Rubenstein,et al.  Dlx1 and Dlx2 Control Neuronal versus Oligodendroglial Cell Fate Acquisition in the Developing Forebrain , 2007, Neuron.

[6]  M. Ekker,et al.  A Subpopulation of Olfactory Bulb GABAergic Interneurons Is Derived from Emx1- and Dlx5/6-Expressing Progenitors , 2007, The Journal of Neuroscience.

[7]  I. Cobos,et al.  Dlx Transcription Factors Promote Migration through Repression of Axon and Dendrite Growth , 2007, Neuron.

[8]  M. Ekker,et al.  Distinct cis-Regulatory Elements from the Dlx1/Dlx2 Locus Mark Different Progenitor Cell Populations in the Ganglionic Eminences and Different Subtypes of Adult Cortical Interneurons , 2007, The Journal of Neuroscience.

[9]  M. Álvarez-Dolado,et al.  Dlx-Dependent and -Independent Regulation of Olfactory Bulb Interneuron Differentiation , 2007, The Journal of Neuroscience.

[10]  S. Ojeda,et al.  Deletion of the Ttf1 Gene in Differentiated Neurons Disrupts Female Reproduction without Impairing Basal Ganglia Function , 2006, The Journal of Neuroscience.

[11]  B. Lee,et al.  TTF-1, a homeodomain-containing transcription factor, regulates feeding behavior in the rat hypothalamus. , 2006, Biochemical and biophysical research communications.

[12]  Beat Lutz,et al.  The Endocannabinoid System Controls Key Epileptogenic Circuits in the Hippocampus , 2006, Neuron.

[13]  F. Guillemot,et al.  Mash1 is required for generic and subtype differentiation of hypothalamic neuroendocrine cells. , 2006, Molecular endocrinology.

[14]  M. Calcagnotto,et al.  Mice lacking Dlx1 show subtype-specific loss of interneurons, reduced inhibition and epilepsy , 2005, Nature Neuroscience.

[15]  R. Cone Anatomy and regulation of the central melanocortin system , 2005, Nature Neuroscience.

[16]  R. Wise,et al.  How can drug addiction help us understand obesity? , 2005, Nature Neuroscience.

[17]  E. Rodríguez,et al.  Hypothalamic tanycytes: a key component of brain-endocrine interaction. , 2005, International review of cytology.

[18]  R. Palmiter,et al.  Dysregulation of Striatal Dopamine Signaling by Amphetamine Inhibits Feeding by Hungry Mice , 2004, Neuron.

[19]  T. Horvath,et al.  The floating blueprint of hypothalamic feeding circuits , 2004, Nature Reviews Neuroscience.

[20]  E. Nillni,et al.  Deletion of the Nhlh2 transcription factor decreases the levels of the anorexigenic peptides alpha melanocyte-stimulating hormone and thyrotropin-releasing hormone and implicates prohormone convertases I and II in obesity. , 2004, Endocrinology.

[21]  T. Hökfelt,et al.  Characterization of neuropeptide Y Y2 and Y5 receptor expression in the mouse hypothalamus , 2004, The Journal of comparative neurology.

[22]  Mitsuru Nishiyama,et al.  GABA Release from Proopiomelanocortin Neurons , 2004, The Journal of Neuroscience.

[23]  T. Kaneko,et al.  Green fluorescent protein expression and colocalization with calretinin, parvalbumin, and somatostatin in the GAD67‐GFP knock‐in mouse , 2003, The Journal of comparative neurology.

[24]  H. Pijl Reduced dopaminergic tone in hypothalamic neural circuits: expression of a "thrifty" genotype underlying the metabolic syndrome? , 2003, European journal of pharmacology.

[25]  Luis Puelles,et al.  Forebrain gene expression domains and the evolving prosomeric model , 2003, Trends in Neurosciences.

[26]  H. Baker,et al.  Dlx‐1 and Dlx‐2 expression in the adult mouse brain: Relationship to dopaminergic phenotypic regulation , 2003, The Journal of comparative neurology.

[27]  J. Rubenstein,et al.  Dlx transcription factors regulate differentiation of dopaminergic neurons of the ventral thalamus , 2003, Molecular and Cellular Neuroscience.

[28]  C. Phelps,et al.  Growth Hormone‐Releasing Hormone‐Producing and Dopaminergic Neurones in the Mouse Arcuate Nucleus Are Independently Regulated Populations , 2003, Journal of neuroendocrinology.

[29]  J. Rubenstein,et al.  Modulation of the notch signaling by Mash1 and Dlx1/2 regulates sequential specification and differentiation of progenitor cell types in the subcortical telencephalon. , 2002, Development.

[30]  C. Saper,et al.  The Need to Feed Homeostatic and Hedonic Control of Eating , 2002, Neuron.

[31]  C. Feierstein,et al.  Disruption of the D2 dopamine receptor alters GH and IGF-I secretion and causes dwarfism in male mice. , 2002, Endocrinology.

[32]  O. Marín,et al.  Patterning of the basal telencephalon and hypothalamus is essential for guidance of cortical projections. , 2002, Development.

[33]  M. Ekker,et al.  Ectopic expression of the Dlx genes induces glutamic acid decarboxylase and Dlx expression. , 2002, Development.

[34]  M. Ekker,et al.  Expression from a Dlx gene enhancer marks adult mouse cortical GABAergic neurons. , 2002, Cerebral cortex.

[35]  M. Collin,et al.  GABAergic Nature of Hypothalamic Leptin Target Neurones in the Ventromedial Arcuate Nucleus , 2001, Journal of neuroendocrinology.

[36]  M. Low,et al.  Leptin activates anorexigenic POMC neurons through a neural network in the arcuate nucleus , 2001, Nature.

[37]  R. Palmiter,et al.  Dopamine Production in the Caudate Putamen Restores Feeding in Dopamine-Deficient Mice , 2001, Neuron.

[38]  M. Costa,et al.  TTF-1, a Homeodomain Gene Required for Diencephalic Morphogenesis, Is Postnatally Expressed in the Neuroendocrine Brain in a Developmentally Regulated and Cell-Specific Fashion , 2001, Molecular and Cellular Neuroscience.

[39]  J. Voogt,et al.  Chapter 12 Regulation of prolactin secretion during pregnancy and lactation , 2001 .

[40]  J. Voogt,et al.  Regulation of prolactin secretion during pregnancy and lactation. , 2001, Progress in brain research.

[41]  Caiying Guo,et al.  Z/EG, a double reporter mouse line that expresses enhanced green fluorescent protein upon cre‐mediated excision , 2000, Genesis.

[42]  S. Anderson,et al.  Origin and Molecular Specification of Striatal Interneurons , 2000, The Journal of Neuroscience.

[43]  S. Woods,et al.  Central nervous system control of food intake , 2000, Nature.

[44]  M. Ekker,et al.  A Highly Conserved Enhancer in the Dlx5/Dlx6Intergenic Region is the Site of Cross-Regulatory Interactions betweenDlx Genes in the Embryonic Forebrain , 2000, The Journal of Neuroscience.

[45]  S. Anderson,et al.  DLX‐1, DLX‐2, and DLX‐5 expression define distinct stages of basal forebrain differentiation , 1999, The Journal of comparative neurology.

[46]  A. Simeone,et al.  Progressive impairment of developing neuroendocrine cell lineages in the hypothalamus of mice lacking the Orthopedia gene. , 1999, Genes & development.

[47]  O. Marín,et al.  Loss of Nkx2.1 homeobox gene function results in a ventral to dorsal molecular respecification within the basal telencephalon: evidence for a transformation of the pallidum into the striatum. , 1999, Development.

[48]  P S Kalra,et al.  Interacting appetite-regulating pathways in the hypothalamic regulation of body weight. , 1999, Endocrine reviews.

[49]  F. Guillemot,et al.  Mash1 regulates neurogenesis in the ventral telencephalon. , 1999, Development.

[50]  Philippe Soriano Generalized lacZ expression with the ROSA26 Cre reporter strain , 1999, Nature Genetics.

[51]  M. Kasuga,et al.  Anxiety-like behavior in transgenic mice with brain expression of neuropeptide Y. , 1998, Proceedings of the Association of American Physicians.

[52]  C. Léránth,et al.  Heterogeneity in the neuropeptide Y-containing neurons of the rat arcuate nucleus: GABAergic and non-GABAergic subpopulations , 1997, Brain Research.

[53]  S. Potter,et al.  Gsh‐1, an orphan Hox gene, is required for normal pituitary development. , 1996, The EMBO journal.

[54]  S. Carroll,et al.  The Development of Crustacean Limbs and the Evolution of Arthropods , 1995, Science.

[55]  J. Rubenstein,et al.  Null mutation of Dlx-2 results in abnormal morphogenesis of proximal first and second branchial arch derivatives and abnormal differentiation in the forebrain. , 1995, Genes & development.