STAT3 Promotes Motor Neuron Differentiation by Collaborating with Motor Neuron-specific LIM Complex

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2013 Jun 27

PMID 23798382

Citations 28

Authors

Seunghee Lee

Rongkun Shen

Hyong-Ho Cho

Ryuk-Jun Kwon

So Yeon Seo

Jae W Lee

Soo-Kyung Lee

Affiliations

Soon will be listed here.

Abstract

The motor neuron (MN)-hexamer complex consisting of LIM homeobox 3, Islet-1, and nuclear LIM interactor is a key determinant of motor neuron specification and differentiation. To gain insights into the transcriptional network in motor neuron development, we performed a genome-wide ChIP-sequencing analysis and found that the MN-hexamer directly regulates a wide array of motor neuron genes by binding to the HxRE (hexamer response element) shared among the target genes. Interestingly, STAT3-binding motif is highly enriched in the MN-hexamer-bound peaks in addition to the HxRE. We also found that a transcriptionally active form of STAT3 is expressed in embryonic motor neurons and that STAT3 associates with the MN-hexamer, enhancing the transcriptional activity of the MN-hexamer in an upstream signal-dependent manner. Correspondingly, STAT3 was needed for motor neuron differentiation in the developing spinal cord. Together, our studies uncover crucial gene regulatory mechanisms that couple MN-hexamer and STAT-activating extracellular signals to promote motor neuron differentiation in vertebrate spinal cord.

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References

Machanick P, Bailey T . MEME-ChIP: motif analysis of large DNA datasets. Bioinformatics. 2011; 27(12):1696-7. PMC: 3106185. DOI: 10.1093/bioinformatics/btr189. View

Lee S, Pfaff S . Synchronization of neurogenesis and motor neuron specification by direct coupling of bHLH and homeodomain transcription factors. Neuron. 2003; 38(5):731-45. DOI: 10.1016/s0896-6273(03)00296-4. View

Oppenheim R, Wiese S, Prevette D, Armanini M, Wang S, Houenou L . Cardiotrophin-1, a muscle-derived cytokine, is required for the survival of subpopulations of developing motoneurons. J Neurosci. 2001; 21(4):1283-91. PMC: 6762241. View

Li M, Sendtner M, Smith A . Essential function of LIF receptor in motor neurons. Nature. 1995; 378(6558):724-7. DOI: 10.1038/378724a0. View

Lee S, Pfaff S . Transcriptional networks regulating neuronal identity in the developing spinal cord. Nat Neurosci. 2001; 4 Suppl:1183-91. DOI: 10.1038/nn750. View

Roelink H, Porter J, Chiang C, Tanabe Y, Chang D, Beachy P . Floor plate and motor neuron induction by different concentrations of the amino-terminal cleavage product of sonic hedgehog autoproteolysis. Cell. 1995; 81(3):445-55. DOI: 10.1016/0092-8674(95)90397-6. View

Joshi K, Lee S, Lee B, Lee J, Lee S . LMO4 controls the balance between excitatory and inhibitory spinal V2 interneurons. Neuron. 2009; 61(6):839-51. PMC: 2848494. DOI: 10.1016/j.neuron.2009.02.011. View

Li H, Durbin R . Fast and accurate short read alignment with Burrows-Wheeler transform. Bioinformatics. 2009; 25(14):1754-60. PMC: 2705234. DOI: 10.1093/bioinformatics/btp324. View

Lee S, Lee B, Joshi K, Pfaff S, Lee J, Lee S . A regulatory network to segregate the identity of neuronal subtypes. Dev Cell. 2008; 14(6):877-89. PMC: 3071743. DOI: 10.1016/j.devcel.2008.03.021. View

10.

Mizuguchi R, Sugimori M, Takebayashi H, Kosako H, Nagao M, Yoshida S . Combinatorial roles of olig2 and neurogenin2 in the coordinated induction of pan-neuronal and subtype-specific properties of motoneurons. Neuron. 2001; 31(5):757-71. DOI: 10.1016/s0896-6273(01)00413-5. View

11.

Darnell Jr J . STATs and gene regulation. Science. 1997; 277(5332):1630-5. DOI: 10.1126/science.277.5332.1630. View

12.

Klug S, Famulok M . All you wanted to know about SELEX. Mol Biol Rep. 1994; 20(2):97-107. DOI: 10.1007/BF00996358. View

13.

Novitch B, Chen A, Jessell T . Coordinate regulation of motor neuron subtype identity and pan-neuronal properties by the bHLH repressor Olig2. Neuron. 2001; 31(5):773-89. DOI: 10.1016/s0896-6273(01)00407-x. View

14.

Pfaff S, Mendelsohn M, Stewart C, Edlund T, Jessell T . Requirement for LIM homeobox gene Isl1 in motor neuron generation reveals a motor neuron-dependent step in interneuron differentiation. Cell. 1996; 84(2):309-20. DOI: 10.1016/s0092-8674(00)80985-x. View

15.

Horvath C . STAT proteins and transcriptional responses to extracellular signals. Trends Biochem Sci. 2000; 25(10):496-502. DOI: 10.1016/s0968-0004(00)01624-8. View

16.

Arber S, Han B, Mendelsohn M, Smith M, Jessell T, Sockanathan S . Requirement for the homeobox gene Hb9 in the consolidation of motor neuron identity. Neuron. 1999; 23(4):659-74. DOI: 10.1016/s0896-6273(01)80026-x. View

17.

Thaler J, Harrison K, Sharma K, Lettieri K, Kehrl J, Pfaff S . Active suppression of interneuron programs within developing motor neurons revealed by analysis of homeodomain factor HB9. Neuron. 1999; 23(4):675-87. DOI: 10.1016/s0896-6273(01)80027-1. View

18.

DeChiara T, Vejsada R, Poueymirou W, Acheson A, Suri C, Conover J . Mice lacking the CNTF receptor, unlike mice lacking CNTF, exhibit profound motor neuron deficits at birth. Cell. 1995; 83(2):313-22. DOI: 10.1016/0092-8674(95)90172-8. View

19.

Bousquet C, Melmed S . Critical role for STAT3 in murine pituitary adrenocorticotropin hormone leukemia inhibitory factor signaling. J Biol Chem. 1999; 274(16):10723-30. DOI: 10.1074/jbc.274.16.10723. View

20.

Dennis Jr G, Sherman B, Hosack D, Yang J, Gao W, Lane H . DAVID: Database for Annotation, Visualization, and Integrated Discovery. Genome Biol. 2003; 4(5):P3. View