Research and Professional Experience
Postdoctoral Fellow/Research Associate, Molecular Biology of the Cell 1, German Cancer Research Centre, Heidelberg, Germany.
Assistant Professor, Department of Neurobiology, University of Pittsburgh School of Medicine, Pittsburgh, PA
Associate Professor, Department of Neurobiology, University of Pittsburgh School of Medicine, Pittsburgh, PA
Molecular Genetic Analysis of the Developmental Basis of Neuropsychiatric Disorders
My laboratory focuses on understanding the molecular and developmental basis of emotional and cognitive behavior and psychiatric illness. The long-term goal of my research is to identify both intrinsic and environmental factors that specifically alter the development of areas in the brain that are essential for emotion and cognition. My laboratory has identified a number of transcriptional repressors (Tlx, Sall1, Sall2, Sall3 and Sall4) that are expressed in the developing forebrain. This research has shown that these genes are express in stem and progenitor cells in the cerebral cortex, and are required to regulate the rate of stem/progenitor cell proliferation and neuronal differentiation. Using both conditional and classical knockout experiments and in-utero electroporation studies in mice, my laboratory has shown that altering the levels of these proteins during development leads to emotional, behavioral and cognitive abnormalities in adult animals. Our most recent studies focus on identifying the cellular and biochemical targets of glucocorticoid action on the developing brain in-utero. Synthetic glucocorticoids are administered to mothers at risk for pre-term labor, to stimulate lung maturation and to reduce the risk of intraventricular hemorrhage and necrotizing enterocolitis. Clinical follow up studies indicate that children exposed to steroid in-utero have cognitive abnormalities and an altered stress response. My laboratory is using a combination of molecular, cellular, proteomic, RNA-Seq. and genome wide DNase hypersensitive site mapping to identify the cellular targets of steroid action. These studies have shown that prenatal exposure to glucocorticoids leads to changes in neuronal number and density in the cerebral cortex at birth coupled to long-term alterations in neurite complexity in the prefrontal cortex and hippocampus in adolescents. These anatomical abnormalities are associated with changes in anxiety and depressive like behaviors in adults. Follow up studies include validating our identified targets in human brain and in umbilical cord blood cells. These findings will for a framework for modifying current clinical dosing regiments in preterm labor to reduce the adverse consequences of premature exposure to corticosteroids in-utero.
Current Research Project(s)
This project examines the developmental basis of neurological abnormalities. Several approaches are used to investigate how environmental or genetic factors influence neural stem cell behavior and how perturbing these processes leads to anatomical and behavioral abnormalities. We are particularly interested in environmental factors that act in-utero such as steroid use, cannabinoids, hypothermia etc. Specific techniques include mouse transgenics, molecular and cellular biology, biochemistry, tissue culture, human umbilical cord blood cell, single nucleotide polymorphism, RNA seq and genetic databases.
Research Resource: The Dexamethasone Transcriptome in Hypothalamic Embryonic Neural Stem Cells.Frahm KA, Peffer ME, Zhang JY, Luthra S, Chakka AB, Couger MB, Chandran UR, Monaghan AP, DeFranco DB. Mol Endocrinol. 2016 Jan;30(1):144-54.
Genome-wide transcript profiling reveals novel breast cancer-associated intronic sense RNAs.Kim SW, Fishilevich E, Arango-Argoty G, Lin Y, Liu G, Li Z, Monaghan AP, Nichols M, John B. PLoS One. 2015 Mar 23;10(3):e0120296..
Caveolin-1 regulates genomic action of the glucocorticoid receptor in neural stem cells.Peffer ME, Chandran UR, Luthra S, Volonte D, Galbiati F, Garabedian MJ, Monaghan AP, DeFranco DB. Mol Cell Biol. 2014 Jul;34(14):2611-23.
Wu P1, Teot L, Murdoch GH, Monaghan-Nichols P, McFadden K. Neuropathology of 22q11 Deletion Syndrome in an Infant. Pediatr Dev Pathol. 2014 17(5):386-92.
An in-depth map of polyadenylation sites in cancer. Lin Y, Li Z, Ozsolak F, Kim SW, Arango-Argoty G, Liu TT, Tenenbaum SA, Bailey T, Monaghan AP, Milos PM, John B. Nucleic Acids Res. 2012 Sep 1;40(17):8460-71.
Sall1 regulates cortical neurogenesis and laminar fate specification in mice: implications for neural abnormalities in Townes-Brocks syndrome. Harrison SJ, Nishinakamura R, Jones KR, Monaghan AP. Dis Model Mech. 2012 May;5(3):351-65.
Comprehensive polyadenylation site maps in yeast and human reveal pervasive alternative polyadenylation. Ozsolak F, Kapranov P, Foissac S, Kim SW, Fishilevich E, Monaghan AP, John B, Milos PM. Cell. 2010 Dec 10;143(6):1018-29. doi: 10.1016/j.cell.
New class of gene-termini-associated human RNAs suggests a novel RNA copying mechanism.Kapranov P, Ozsolak F, Kim SW, Foissac S, Lipson D, Hart C, Roels S, Borel C, Antonarakis SE, Monaghan AP, John B, Milos PM. Nature. 2010 Jul 29;466(7306):642-6. doi: 10.1038/nature09190.
Sall3 is required for the terminal maturation of olfactory glomerular interneurons.Harrison SJ, Parrish M, Monaghan AP. J Comp Neurol. 2008 Apr 10;507(5):1780-94.
Sall1 regulates mitral cell development and olfactory nerve extension in the developing olfactory bulb. Harrison SJ, Nishinakamura R, Monaghan AP. Cereb Cortex. 2008 Jul;18(7):1604-17.
Abnormal development of zinc-containing cortical circuits in the absence of the transcription factor Tailless. Land PW, Monaghan AP. Brain Res Dev Brain Res. 2005 Aug 8;158(1-2):97-101.
The Tlx gene regulates the timing of neurogenesis in the cortex. Roy K, Kuznicki K, Wu Q, Sun Z, Bock D, Schutz G, Vranich N, Monaghan AP. J Neurosci. 2004 Sep 22;24(38):8333-45.
Loss of the Sall3 gene leads to palate deficiency, abnormalities in cranial nerves, and perinatal lethality. Parrish M, Ott T, Lance-Jones C, Schuetz G, Schwaeger-Nickolenko A, Monaghan AP. Mol Cell Biol. 2004 Aug;24(16):7102-12.
Expression of the transcription factor, tailless, is required for formation of superficial cortical layers. Land PW, Monaghan AP. Cereb Cortex. 2003 Sep;13(9):921-31.
Loss of the tailless gene affects forebrain development and emotional behavior. Roy K, Thiels E, Monaghan AP. Physiol Behav. 2002 Dec;77(4-5):595-600.
A new member of the spalt like zinc finger protein family, Msal-3, is expressed in the CNS and sites of epithelial/mesenchymal interaction. Ott T, Parrish M, Bond K, Schwaeger-Nickolenko A, Monaghan AP.= Mech Dev. 2001 Mar;101(1-2):203-7.
Defective limbic system in mice lacking the tailless gene. Monaghan AP, Bock D, Gass P, Schwäger A, Wolfer DP, Lipp HP, Schütz G. Nature. 1997 Dec 4;390(6659):515-7.