Overexpression of Neurotrophin 4 in Skin Enhances Myelinated Sensory Endings but Does Not Influence Sensory Neuron Number

Overview

Journal J Comp Neurol

Specialty Neurology

Date 2006 Aug 29

PMID 16937395

Citations 13

Authors

Robin F Krimm

Brian M Davis

Teresa Noel

Kathryn M Albers

Affiliations

Soon will be listed here.

Abstract

The growth factors neurotrophin 4 (NT4) and brain-derived neurotrophic factor (BDNF) are expressed in the developing skin, activate the trkB tyrosine kinase receptor, and influence the development and survival of specific types of sensory afferents. Whether each factor is capable of regulating the same or overlapping populations of cutaneous afferents during development is unknown. A previous study of mice overexpressing BDNF in the developing skin (BDNF-OE mice) revealed that these animals exhibited increased hair follicle innervation, Meissner corpuscle size, and Merkel cell number in glabrous skin, although no change in the total number of sensory neurons was observed. To determine if NT4 affects cutaneous innervation in a manner similar to BDNF, transgenic mice overexpressing NT4 in skin, under the control of the keratin 14 gene promoter, were examined. Similar to BDNF-OE mice, NT4-OE mice had increased innervation to the skin but no increase in sensory neuron number in either the dorsal root ganglion or trigeminal ganglion. NT4 overexpression also enhanced hair follicle innervation and the size and density of innervation to Meissner corpuscles. Unlike BDNF overexpression, NT4 overexpression did not alter the number of Merkel cells in the glabrous skin, but it did enhance the number of myelinated axons in nerves projecting to skin. Thus, the same pattern of BDNF and NT4 overexpression within the skin produces phenotypes that are both similar and distinctive.

Citing Articles

Molecular regulation of axon termination in mechanosensory neurons.

Desbois M, Grill B Development. 2024; 151(17).

PMID: 39268828 PMC: 11698068. DOI: 10.1242/dev.202945.

The Lamellar Cells of Vertebrate Meissner and Pacinian Corpuscles: Development, Characterization, and Functions.

Suazo I, Vega J, Garcia-Mesa Y, Garcia-Piqueras J, Garcia-Suarez O, Cobo T Front Neurosci. 2022; 16:790130.

PMID: 35356056 PMC: 8959428. DOI: 10.3389/fnins.2022.790130.

Evaluation of serum levels of neurotrophin 4 and brain-derived nerve growth factor in uremic pruritus patients.

Sorour N, Elesawy F, Tabl H, Ibrahim M, Akl E Clin Cosmet Investig Dermatol. 2019; 12:109-114.

PMID: 30799944 PMC: 6371925. DOI: 10.2147/CCID.S190917.

Automated PGP9.5 immunofluorescence staining: a valuable tool in the assessment of small fiber neuropathy?.

Van Acker N, Rage M, Sluydts E, Knaapen M, De Bie M, Timmers M BMC Res Notes. 2016; 9:280.

PMID: 27215701 PMC: 4878004. DOI: 10.1186/s13104-016-2085-4.

The specification and wiring of mammalian cutaneous low-threshold mechanoreceptors.

Olson W, Dong P, Fleming M, Luo W Wiley Interdiscip Rev Dev Biol. 2016; 5(3):389-404.

PMID: 26992078 PMC: 4864430. DOI: 10.1002/wdev.229.

References

Mills L, Nurse C, Diamond J . The neural dependency of Merkel cell development in the rat: the touch domes and foot pads contrasted. Dev Biol. 1989; 136(1):61-74. DOI: 10.1016/0012-1606(89)90130-9. View

Krimm R, Davis B, Woodbury C, Albers K . NT3 expressed in skin causes enhancement of SA1 sensory neurons that leads to postnatal enhancement of Merkel cells. J Comp Neurol. 2004; 471(3):352-60. DOI: 10.1002/cne.20041. View

Figueiredo H, Davis B, Albers K . Skin-derived nerve growth factor blocks programmed cell death in the trigeminal ganglia but does not enhance neuron proliferation. Mech Dev. 2001; 109(2):205-14. DOI: 10.1016/s0925-4773(01)00525-1. View

Airaksinen M, Koltzenburg M, Lewin G, Masu Y, Helbig C, Wolf E . Specific subtypes of cutaneous mechanoreceptors require neurotrophin-3 following peripheral target innervation. Neuron. 1996; 16(2):287-95. DOI: 10.1016/s0896-6273(00)80047-1. View

Yacoubian T, Lo D . Truncated and full-length TrkB receptors regulate distinct modes of dendritic growth. Nat Neurosci. 2000; 3(4):342-9. DOI: 10.1038/73911. View

Moll I, Kuhn C, Moll R . Cytokeratin 20 is a general marker of cutaneous Merkel cells while certain neuronal proteins are absent. J Invest Dermatol. 1995; 104(6):910-5. DOI: 10.1111/1523-1747.ep12606183. View

Fundin B, Silos-Santiago I, Ernfors P, Fagan A, Aldskogius H, DeChiara T . Differential dependency of cutaneous mechanoreceptors on neurotrophins, trk receptors, and P75 LNGFR. Dev Biol. 1997; 190(1):94-116. DOI: 10.1006/dbio.1997.8658. View

Minichiello L, Calella A, Medina D, Bonhoeffer T, Klein R, Korte M . Mechanism of TrkB-mediated hippocampal long-term potentiation. Neuron. 2002; 36(1):121-37. DOI: 10.1016/s0896-6273(02)00942-x. View

Gonzalez-Martinez T, Germana G, Monjil D, Silos-Santiago I, de Carlos F, Germana G . Absence of Meissner corpuscles in the digital pads of mice lacking functional TrkB. Brain Res. 2004; 1002(1-2):120-8. DOI: 10.1016/j.brainres.2004.01.003. View

10.

Gonzalez-Martinez T, Farinas I, Del Valle M, Feito J, Germana G, Cobo J . BDNF, but not NT-4, is necessary for normal development of Meissner corpuscles. Neurosci Lett. 2005; 377(1):12-5. DOI: 10.1016/j.neulet.2004.11.078. View

11.

Liebl D, Tessarollo L, Palko M, Parada L . Absence of sensory neurons before target innervation in brain-derived neurotrophic factor-, neurotrophin 3-, and TrkC-deficient embryonic mice. J Neurosci. 1997; 17(23):9113-21. PMC: 6573597. View

12.

Liebl D, Klesse L, Tessarollo L, Wohlman T, Parada L . Loss of brain-derived neurotrophic factor-dependent neural crest-derived sensory neurons in neurotrophin-4 mutant mice. Proc Natl Acad Sci U S A. 2000; 97(5):2297-302. PMC: 15795. DOI: 10.1073/pnas.040562597. View

13.

Conover J, Erickson J, Katz D, Bianchi L, Poueymirou W, McClain J . Neuronal deficits, not involving motor neurons, in mice lacking BDNF and/or NT4. Nature. 1995; 375(6528):235-8. DOI: 10.1038/375235a0. View

14.

Davis B, Fundin B, Albers K, Goodness T, Cronk K, Rice F . Overexpression of nerve growth factor in skin causes preferential increases among innervation to specific sensory targets. J Comp Neurol. 1997; 387(4):489-506. DOI: 10.1002/(sici)1096-9861(19971103)387:4<489::aid-cne2>3.0.co;2-z. View

15.

Szeder V, Grim M, Kucera J, Sieber-Blum M . Neurotrophin-3 signaling in mammalian Merkel cell development. Dev Dyn. 2003; 228(4):623-9. DOI: 10.1002/dvdy.10403. View

16.

Fraser S . Effects of brain-derived neurotrophic factor on optic axon branching and remodelling in vivo. Nature. 1995; 378(6553):192-6. DOI: 10.1038/378192a0. View

17.

Fan G, Egles C, Sun Y, Minichiello L, Renger J, Klein R . Knocking the NT4 gene into the BDNF locus rescues BDNF deficient mice and reveals distinct NT4 and BDNF activities. Nat Neurosci. 2000; 3(4):350-7. DOI: 10.1038/73921. View

18.

Stucky C, Koltzenburg M, Schneider M, Engle M, Albers K, Davis B . Overexpression of nerve growth factor in skin selectively affects the survival and functional properties of nociceptors. J Neurosci. 1999; 19(19):8509-16. PMC: 6783005. View

19.

Krimm R, Davis B, Albers K . Cutaneous overexpression of neurotrophin-3 (NT3) selectively restores sensory innervation in NT3 gene knockout mice. J Neurobiol. 2000; 43(1):40-9. DOI: 10.1002/(sici)1097-4695(200004)43:1<40::aid-neu4>3.0.co;2-r. View

20.

Lopez G, Krimm R . Epithelial overexpression of BDNF and NT4 produces distinct gustatory axon morphologies that disrupt initial targeting. Dev Biol. 2006; 292(2):457-68. PMC: 1939808. DOI: 10.1016/j.ydbio.2006.01.021. View