Differentiation and Localization of Interneurons in the Developing Spinal Cord Depends on DOT1L Expression

Overview

Journal Mol Brain

Publisher Biomed Central

Specialties Molecular Biology
Neurology

Date 2020 May 31

PMID 32471461

Citations 5

Authors

Angelica Gray de Cristoforis

Francesco Ferrari

Frederic Clotman

Tanja Vogel

Affiliations

Soon will be listed here.

Abstract

Genetic and epigenetic factors contribute to the development of the spinal cord. Failure in correct exertion of the developmental programs, including neurulation, neural tube closure and neurogenesis of the diverse spinal cord neuronal subtypes results in defects of variable severity. We here report on the histone methyltransferase Disruptor of Telomeric 1 Like (DOT1L), which mediates histone H3 lysine 79 (H3K79) methylation. Conditional inactivation of DOT1L using Wnt1-cre as driver (Dot1l-cKO) showed that DOT1L expression is essential for spinal cord neurogenesis and localization of diverse neuronal subtypes, similar to its function in the development of the cerebral cortex and cerebellum. Transcriptome analysis revealed that DOT1L deficiency favored differentiation over progenitor proliferation. Dot1l-cKO mainly decreased the numbers of dI1 interneurons expressing Lhx2. In contrast, Lhx9 expressing dI1 interneurons did not change in numbers but localized differently upon Dot1l-cKO. Similarly, loss of DOT1L affected localization but not generation of dI2, dI3, dI5, V0 and V1 interneurons. The resulting derailed interneuron patterns might be responsible for increased cell death, occurrence of which was restricted to the late developmental stage E18.5. Together our data indicate that DOT1L is essential for subtype-specific neurogenesis, migration and localization of dorsal and ventral interneurons in the developing spinal cord, in part by regulating transcriptional activation of Lhx2.

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References

Castano Betancourt M, Cailotto F, Kerkhof H, Cornelis F, Doherty S, Hart D . Genome-wide association and functional studies identify the DOT1L gene to be involved in cartilage thickness and hip osteoarthritis. Proc Natl Acad Sci U S A. 2012; 109(21):8218-23. PMC: 3361426. DOI: 10.1073/pnas.1119899109. View

Liu Z, Hu X, Huang C, Zheng K, Takebayashi H, Cao C . Olig3 is not involved in the ventral patterning of spinal cord. PLoS One. 2014; 9(10):e111076. PMC: 4211884. DOI: 10.1371/journal.pone.0111076. View

Prasad T, Wang X, Gray P, Weiner J . A differential developmental pattern of spinal interneuron apoptosis during synaptogenesis: insights from genetic analyses of the protocadherin-gamma gene cluster. Development. 2008; 135(24):4153-64. PMC: 2755264. DOI: 10.1242/dev.026807. View

Liao Y, Smyth G, Shi W . The R package Rsubread is easier, faster, cheaper and better for alignment and quantification of RNA sequencing reads. Nucleic Acids Res. 2019; 47(8):e47. PMC: 6486549. DOI: 10.1093/nar/gkz114. View

Wilson S, Shafer B, Lee K, Dodd J . A molecular program for contralateral trajectory: Rig-1 control by LIM homeodomain transcription factors. Neuron. 2008; 59(3):413-24. DOI: 10.1016/j.neuron.2008.07.020. View

Hernandez-Miranda L, Muller T, Birchmeier C . The dorsal spinal cord and hindbrain: From developmental mechanisms to functional circuits. Dev Biol. 2016; 432(1):34-42. DOI: 10.1016/j.ydbio.2016.10.008. View

Fink A, Croce K, Huang Z, Abbott L, Jessell T, Azim E . Presynaptic inhibition of spinal sensory feedback ensures smooth movement. Nature. 2014; 509(7498):43-8. PMC: 4292914. DOI: 10.1038/nature13276. View

Phelps P, Rich R, Rios Y, Wong T . Evidence for a cell-specific action of Reelin in the spinal cord. Dev Biol. 2002; 244(1):180-98. DOI: 10.1006/dbio.2002.0580. View

Lu D, Niu T, Alaynick W . Molecular and cellular development of spinal cord locomotor circuitry. Front Mol Neurosci. 2015; 8:25. PMC: 4468382. DOI: 10.3389/fnmol.2015.00025. View

10.

Chen Y, Auer-Grumbach M, Matsukawa S, Zitzelsberger M, Themistocleous A, Strom T . Transcriptional regulator PRDM12 is essential for human pain perception. Nat Genet. 2015; 47(7):803-8. PMC: 7212047. DOI: 10.1038/ng.3308. View

11.

Pillai A, Mansouri A, Behringer R, Westphal H, Goulding M . Lhx1 and Lhx5 maintain the inhibitory-neurotransmitter status of interneurons in the dorsal spinal cord. Development. 2006; 134(2):357-66. DOI: 10.1242/dev.02717. View

12.

Leek J, Johnson W, Parker H, Jaffe A, Storey J . The sva package for removing batch effects and other unwanted variation in high-throughput experiments. Bioinformatics. 2012; 28(6):882-3. PMC: 3307112. DOI: 10.1093/bioinformatics/bts034. View

13.

Zhang Q, Xue P, Li H, Bao Y, Wu L, Chang S . Histone modification mapping in human brain reveals aberrant expression of histone H3 lysine 79 dimethylation in neural tube defects. Neurobiol Dis. 2013; 54:404-13. DOI: 10.1016/j.nbd.2013.01.014. View

14.

Gross M, Dottori M, Goulding M . Lbx1 specifies somatosensory association interneurons in the dorsal spinal cord. Neuron. 2002; 34(4):535-49. DOI: 10.1016/s0896-6273(02)00690-6. View

15.

Franz H, Villarreal A, Heidrich S, Videm P, Kilpert F, Mestres I . DOT1L promotes progenitor proliferation and primes neuronal layer identity in the developing cerebral cortex. Nucleic Acids Res. 2018; 47(1):168-183. PMC: 6326801. DOI: 10.1093/nar/gky953. View

16.

Delile J, Rayon T, Melchionda M, Edwards A, Briscoe J, Sagner A . Single cell transcriptomics reveals spatial and temporal dynamics of gene expression in the developing mouse spinal cord. Development. 2019; 146(12). PMC: 6602353. DOI: 10.1242/dev.173807. View

17.

Feng Y, Yang Y, Ortega M, Copeland J, Zhang M, Jacob J . Early mammalian erythropoiesis requires the Dot1L methyltransferase. Blood. 2010; 116(22):4483-91. PMC: 3321834. DOI: 10.1182/blood-2010-03-276501. View

18.

Bhardwaj V, Heyne S, Sikora K, Rabbani L, Rauer M, Kilpert F . snakePipes: facilitating flexible, scalable and integrative epigenomic analysis. Bioinformatics. 2019; 35(22):4757-4759. PMC: 6853707. DOI: 10.1093/bioinformatics/btz436. View

19.

Zhang Q, Bai B, Mei X, Wan C, Cao H, Li D . Elevated H3K79 homocysteinylation causes abnormal gene expression during neural development and subsequent neural tube defects. Nat Commun. 2018; 9(1):3436. PMC: 6109101. DOI: 10.1038/s41467-018-05451-7. View

20.

Buttner N, Johnsen S, Kugler S, Vogel T . Af9/Mllt3 interferes with Tbr1 expression through epigenetic modification of histone H3K79 during development of the cerebral cortex. Proc Natl Acad Sci U S A. 2010; 107(15):7042-7. PMC: 2872432. DOI: 10.1073/pnas.0912041107. View