Home » Newsroom » Research Newsletter » Research Newsletter - November 2006

Research Newsletter - November 2006

Spotlight

In a paper published in Nature Neuroscience, two investigators from the Harvard Stem Cell Institute and Massachusetts General Hospital describe how insulin-like growth factor 1 (IGF-1) dramatically increases the in vitro growth of corticospinal motor neuron (CSMN) axons - projections that carry nerve impulses to the spinal motor neurons that connect to muscles - and that blocking IGF-1 activity reduces that growth in both cultured cells and in living mice.

"Our findings that IGF-1 specifically enhances both the speed and extent of axon outgrowth of corticospinal motor neurons are the first direct evidence of growth factor control over the differentiation of these neurons," says Jeffrey Macklis MD, DHST, leader of HSCI's Nervous System Diseases Program. "In addition to providing insight into the development and circuit formation of this critical population of neurons, these results might lead to the future ability to treat motor neuron disorders and spinal cord injuries."

Although their cell bodies are located in the brain, CSMN axons extend down to the neurons they control in the spinal cord - extending as far as three feet in adult humans. These neurons degenerate in ALS and related disorders, and their damage contributes to loss of motor function in spinal cord injuries. Because CSMN are embedded among hundreds of other types of neurons in the cerebral cortex, it has been difficult to study these cells, and little is known about cellular and molecular factors that control their growth and development. In order to study growth factor controls over these cells, Macklis and Hande Ozdinler, PhD, a postdoctoral fellow in his laboratory, developed a new way of isolating pure populations of CSMN in culture and found that IGF-1 was a prime candidate for control over CSMN development.

The team showed that if IGF-1 was applied to a pure population of CSMN, either by generally adding it to culture dishes or placing IGF-1-coated microbeads right next to CSMN cell bodies, the growth of axons increased by 15- to 20-fold, reaching rates previously seen only during initial development. Blocking the interaction between IGF-1 and its receptor reduced axon growth to control levels, confirming that the IGF-1 pathway is critical to the enhancement effect.

Experiments with another type of neuron and with several different growth factors verified that axonal growth was stimulated only by IGF-1 and only in CSMN. The researchers also showed that IGF-1 enhancement of axonal growth operates separately from the growth factors known support of neuronal survival. Tests in living developing mice showed that blocking the IGF-1 pathway in the spinal cord prevented the growth of CSMN axons, which confirmed the applicability of the in vitro experiments to living mammals.

"The role of IGF-1 as a potent and specific enhancer of CSMN axon growth is highly relevant to our understanding of this critical population of neurons," says Macklis. "These findings are a first step that may someday lead to ways of treating the neuronal degeneration of diseases like ALS, regenerating cells for the treatment of spinal cord injury, and to the potential replacement of neurons using precursors or 'neural stem cells'."

Ozdinler PH, Macklis JD. IGF-I specifically enhances axon outgrowth of corticospinal motor neurons. Nat Neurosci. 2006 Nov;9(11):1371-1381. Read Abstract.

Scientific Papers

Review and Commentary

  • Sosnovik DE, Weissleder R. Emerging concepts in molecular MRI. Curr Opin Biotechnol. 2006 Nov 23 Read Abstract.

Blood

  • Iwasaki H, Mizuno S, Arinobu Y, Ozawa H, Mori Y, Shigematsu H, Takatsu K, Tenen DG, Akashi K. The order of expression of transcription factors directs hierarchical specification of hematopoietic lineages. Genes Dev. 2006 Nov 1;20(21):3010-21. Read Abstract.
  • Zada AA, Geletu MH, Pulikkan JA, Muller-Tidow C, Reddy VA, Christopeit M, Hiddemann WD, Behre HM, Tenen DG, Behre G. Proteomic analysis of acute promyelocytic leukemia: PML-RARalpha leads to decreased phosphorylation of OP18 at serine 63. Proteomics. 2006 Nov;6(21):5705-19. Read Abstract.
  • Zada AA, Pulikkan JA, Bararia D, Geletu M, Trivedi AK, Balkhi MY, Hiddemann WD, Tenen DG, Behre HM, Behre G. Proteomic discovery of Max as a novel interacting partner of C/EBPalpha: a Myc/Max/Mad link. Leukemia. 2006 Dec;20(12):2137-46. Read Abstract.

Cancer

  • Pieretti-Vanmarcke R, Donahoe PK, Pearsall LA, Dinulescu DM, Connolly DC, Halpern EF, Seiden MV, Maclaughlin DT. Mullerian Inhibiting Substance enhances subclinical doses of chemotherapeutic agents to inhibit human and mouse ovarian cancer. Proc Natl Acad Sci USA. 2006 Nov 14;103(46):17426-17431. Read Abstract.

Cardiovascular System

  • Hoshijima M, Knoll R, Pashmforoush M, Chien KR. Reversal of calcium cycling defects in advanced heart failure toward molecular therapy. J Am Coll Cardiol. 2006 Nov 7;48(9 Suppl):A15-23. Read Abstract.
  • Moretti A, Caron L, Nakano A, Lam JT, Bernshausen A, Chen Y, Qyang Y, Bu L, Sasaki M, Martin-Puig S, Sun Y, Evans SM, Laugwitz KL, Chien KR. Multipotent Embryonic Isl1(+) Progenitor Cells Lead to Cardiac, Smooth Muscle, and Endothelial Cell Diversification. Cell. 2006 Nov 20; Read Abstract.
  • Smart N, Risebro CA, Melville AA, Moses K, Schwartz RJ, Chien KR, Riley PR. Thymosin beta4 induces adult epicardial progenitor mobilization and neovascularization. Nature. 2006 Nov 15; Read Abstract.
  • Wu SM, Fujiwara Y, Cibulsky SM, Clapham DE, Lien CL, Schultheiss TM, Orkin SH. Developmental Origin of a Bipotential Myocardial and Smooth Muscle Cell Precursor in the Mammalian Heart. Cell. 2006 Nov 20 Read Abstract.
  • Yajima T, Yasukawa H, Jeon ES, Xiong D, Dorner A, Iwatate M, Nara M, Zhou H, Summers-Torres D, Hoshijima M, Chien KR, Yoshimura A, Knowlton KU. Innate defense mechanism against virus infection within the cardiac myocyte requiring gp130-STAT3 signaling. Circulation. 2006 Nov 28;114(22):2364-73. Read Abstract.

Developmental Biology

  • Mishima Y, Giraldez AJ, Takeda Y, Fujiwara T, Sakamoto H, Schier AF, Inoue K. Differential Regulation of Germline mRNAs in Soma and Germ Cells by Zebrafish miR-430. Curr Biol. 2006 Nov 7;16(21):2135-42. Read Abstract.
  • Wang J, Rao S, Chu J, Shen X, Levasseur DN, Theunissen TW, Orkin SH. A protein interaction network for pluripotency of embryonic stem cells. Nature. 2006 Nov 16;444(7117):364-8. Read Abstract.

Immunology

  • Campanella GS, Grimm J, Manice LA, Colvin RA, Medoff BD, Wojtkiewicz GR, Weissleder R, Luster AD. Oligomerization of CXCL10 Is Necessary for Endothelial Cell Presentation and In Vivo Activity. J Immunol. 2006 Nov 15;177(10):6991-8. Read Abstract.
  • Duffield JS, Hong S, Vaidya VS, Lu Y, Fredman G, Serhan CN, Bonventre JV. Resolvin D series and protectin D1 mitigate acute kidney injury. J Immunol. 2006 Nov 1;177(9):5902-11. Read Abstract.

Nervous System

  • Liu L, Zhao R, Bai Y, Stanish LF, Evans JE, Sanderson MJ, Bonventre JV, Rittenhouse AR. M1 muscarinic receptors inhibit L-type Ca2+ current and M-current by divergent signal transduction cascades. J Neurosci. 2006 Nov 8;26(45):11588-98. Read Abstract.

Skeletal System

  • Lam NP, Li Y, Waldman AB, Brussiau J, Lee PL, Olsen BR, Xu L. Age-dependent increase of discoidin domain receptor 2 and matrix metalloproteinase 13 expression in temporomandibular joint cartilage of type IX and type XI collagen-deficient mice. Arch Oral Biol. 2006 Nov 22 Read Abstract.