Genetic and Functional Modularity of Activities in the Specification of Limb-Innervating Motor Neurons

English version České info

A critical step in the assembly of the neural circuits that control tetrapod locomotion is the specification of the lateral motor column (LMC), a diverse motor neuron population targeting limb musculature. Hox6 paralog group genes have been implicated as key determinants of LMC fate at forelimb levels of the spinal cord, through their ability to promote expression of the LMC-restricted genes Foxp1 and Raldh2 and to suppress thoracic fates through exclusion of Hoxc9. The specific roles and mechanisms of Hox6 gene function in LMC neurons, however, are not known. We show that Hox6 genes are critical for diverse facets of LMC identity and define motifs required for their in vivo specificities. Although Hox6 genes are necessary for generating the appropriate number of LMC neurons, they are not absolutely required for the induction of forelimb LMC molecular determinants. In the absence of Hox6 activity, LMC identity appears to be preserved through a diverse array of Hox5–Hox8 paralogs, which are sufficient to reprogram thoracic motor neurons to an LMC fate. In contrast to the apparently permissive Hox inputs to early LMC gene programs, individual Hox genes, such as Hoxc6, have specific roles in promoting motor neuron pool diversity within the LMC. Dissection of motifs required for Hox in vivo specificities reveals that either cross-repressive interactions or cooperativity with Pbx cofactors are sufficient to induce LMC identity, with the N-terminus capable of promoting columnar, but not pool, identity when transferred to a heterologous homeodomain. These results indicate that Hox proteins orchestrate diverse aspects of cell fate specification through both the convergent regulation of gene programs regulated by many paralogs and also more restricted actions encoded through specificity determinants in the N-terminus.

Vyšlo v časopise: Genetic and Functional Modularity of Activities in the Specification of Limb-Innervating Motor Neurons. PLoS Genet 9(1): e32767. doi:10.1371/journal.pgen.1003184
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1003184

Souhrn

Zdroje

1. GutmanCR, AjmeraMK, HollydayM (1993) Organization of motor pools supplying axial muscles in the chicken. Brain Res 609: 129–136.

2. LandmesserLT (2001) The acquisition of motoneuron subtype identity and motor circuit formation. Int J Dev Neurosci 19: 175–182.

3. LandmesserL (1978) The development of motor projection patterns in the chick hind limb. J Physiol 284: 391–414.

4. TosneyKW, LandmesserLT (1985) Development of the major pathways for neurite outgrowth in the chick hindlimb. Dev Biol 109: 193–214.

5. HollydayM, JacobsonRD (1990) Location of motor pools innervating chick wing. J Comp Neurol 302: 575–588.

6. LandmesserL (1978) The distribution of motoneurones supplying chick hind limb muscles. J Physiol 284: 371–389.

7. RomanesGJ (1942) The development and significance of the cell columns in the ventral horn of the cervical and upper thoracic spinal cord of the rabbit. J Anat Lond 76: 112–130.

8. Dalla Torre di SanguinettoSA, DasenJS, ArberS (2008) Transcriptional mechanisms controlling motor neuron diversity and connectivity. Curr Opin Neurobiol 18: 36–43.

9. DasenJS, JessellTM (2009) Hox networks and the origins of motor neuron diversity. Curr Top Dev Biol 88: 169–200.

10. DasenJS, TiceBC, Brenner-MortonS, JessellTM (2005) A Hox regulatory network establishes motor neuron pool identity and target-muscle connectivity. Cell 123: 477–491.

11. DasenJS, LiuJP, JessellTM (2003) Motor neuron columnar fate imposed by sequential phases of Hox-c activity. Nature 425: 926–933.

12. ShahV, DrillE, Lance-JonesC (2004) Ectopic expression of Hoxd10 in thoracic spinal segments induces motoneurons with a lumbosacral molecular profile and axon projections to the limb. Dev Dyn 231: 43–56.

13. WuY, WangG, ScottSA, CapecchiMR (2008) Hoxc10 and Hoxd10 regulate mouse columnar, divisional and motor pool identity of lumbar motoneurons. Development 135: 171–182.

14. De Marco GarciaNV, JessellTM (2008) Early Motor Neuron Pool Identity and Muscle Nerve Trajectory Defined by Postmitotic Restrictions in Nkx6.1 Activity. Neuron 57: 217–231.

15. TarchiniB, HuynhTH, CoxGA, DubouleD (2005) HoxD cluster scanning deletions identify multiple defects leading to paralysis in the mouse mutant Ironside. Genes Dev 19: 2862–2876.

16. VermotJ, SchuhbaurB, Le MouellicH, McCafferyP, GarnierJM, et al. (2005) Retinaldehyde dehydrogenase 2 and Hoxc8 are required in the murine brachial spinal cord for the specification of Lim1+ motoneurons and the correct distribution of Islet1+ motoneurons. Development 132: 1611–1621.

17. MannRS, LelliKM, JoshiR (2009) Hox specificity unique roles for cofactors and collaborators. Current topics in developmental biology 88: 63–101.

18. MoensCB, SelleriL (2006) Hox cofactors in vertebrate development. Developmental biology 291: 193–206.

19. ChangCP, BrocchieriL, ShenWF, LargmanC, ClearyML (1996) Pbx modulation of Hox homeodomain amino-terminal arms establishes different DNA-binding specificities across the Hox locus. Molecular and cellular biology 16: 1734–1745.

20. NeuteboomST, MurreC (1997) Pbx raises the DNA binding specificity but not the selectivity of antennapedia Hox proteins. Molecular and cellular biology 17: 4696–4706.

21. SlatteryM, RileyT, LiuP, AbeN, Gomez-AlcalaP, et al. (2011) Cofactor binding evokes latent differences in DNA binding specificity between Hox proteins. Cell 147: 1270–1282.

22. JoshiR, PassnerJM, RohsR, JainR, SosinskyA, et al. (2007) Functional specificity of a Hox protein mediated by the recognition of minor groove structure. Cell 131: 530–543.

23. JoshiR, SunL, MannR (2010) Dissecting the functional specificities of two Hox proteins. Genes Dev 24: 1533–1545.

24. GebeleinB, McKayDJ, MannRS (2004) Direct integration of Hox and segmentation gene inputs during Drosophila development. Nature 431: 653–659.

25. WalshCM, CarrollSB (2007) Collaboration between Smads and a Hox protein in target gene repression. Development 134: 3585–3592.

26. JungH, LacombeJ, MazzoniEO, LiemKFJr, GrinsteinJ, et al. (2010) Global control of motor neuron topography mediated by the repressive actions of a single hox gene. Neuron 67: 781–796.

27. LiuJP, LauferE, JessellTM (2001) Assigning the positional identity of spinal motor neurons: rostrocaudal patterning of Hox-c expression by FGFs, Gdf11, and retinoids. Neuron 32: 997–1012.

28. DasenJS, De CamilliA, WangB, TuckerPW, JessellTM (2008) Hox repertoires for motor neuron diversity and connectivity gated by a single accessory factor, FoxP1. Cell 134: 304–316.

29. RoussoDL, GaberZB, WellikD, MorriseyEE, NovitchBG (2008) Coordinated actions of the forkhead protein Foxp1 and Hox proteins in the columnar organization of spinal motor neurons. Neuron 59: 226–240.

30. KaniaA, JessellTM (2003) Topographic motor projections in the limb imposed by LIM homeodomain protein regulation of ephrin-A:EphA interactions. Neuron 38: 581–596.

31. SockanathanS, JessellTM (1998) Motor neuron-derived retinoid signaling specifies the subtype identity of spinal motor neurons. Cell 94: 503–514.

32. Garcia-GascaA, SpyropoulosDD (2000) Differential mammary morphogenesis along the anteroposterior axis in Hoxc6 gene targeted mice. Dev Dyn 219: 261–276.

33. McIntyreDC, RakshitS, YallowitzAR, LokenL, JeannotteL, et al. (2007) Hox patterning of the vertebrate rib cage. Development 134: 2981–2989.

34. CohenS, FunkelsteinL, LivetJ, RougonG, HendersonCE, et al. (2005) A semaphorin code defines subpopulations of spinal motor neurons during mouse development. Eur J Neurosci 21: 1767–1776.

35. LivetJ, SigristM, StroebelS, De PaolaV, PriceSR, et al. (2002) ETS gene Pea3 controls the central position and terminal arborization of specific motor neuron pools. Neuron 35: 877–892.

36. ArberS, HanB, MendelsohnM, SmithM, JessellTM, et al. (1999) Requirement for the homeobox gene Hb9 in the consolidation of motor neuron identity. Neuron 23: 659–674.

37. WichterleH, LieberamI, PorterJA, JessellTM (2002) Directed differentiation of embryonic stem cells into motor neurons. Cell 110: 385–397.

38. TourE, HittingerCT, McGinnisW (2005) Evolutionarily conserved domains required for activation and repression functions of the Drosophila Hox protein Ultrabithorax. Development 132: 5271–5281.

39. YallowitzAR, GongKQ, SwinehartIT, NelsonLT, WellikDM (2009) Non-homeodomain regions of Hox proteins mediate activation versus repression of Six2 via a single enhancer site in vivo. Developmental biology 335: 156–165.

40. MerabetS, KambrisZ, CapovillaM, BerengerH, PradelJ, et al. (2003) The hexapeptide and linker regions of the AbdA Hox protein regulate its activating and repressive functions. Dev Cell 4: 761–768.

41. ViselA, MinovitskyS, DubchakI, PennacchioLA (2007) VISTA Enhancer Browser–a database of tissue-specific human enhancers. Nucleic acids research 35: D88–92.

42. RyooHD, MannRS (1999) The control of trunk Hox specificity and activity by Extradenticle. Genes Dev 13: 1704–1716.

43. DavidsonAJ, ErnstP, WangY, DekensMP, KingsleyPD, et al. (2003) cdx4 mutants fail to specify blood progenitors and can be rescued by multiple hox genes. Nature 425: 300–306.

44. HudryB, RemacleS, DelfiniMC, RezsohazyR, GrabaY, et al. (2012) Hox Proteins Display a Common and Ancestral Ability to Diversify Their Interaction Mode with the PBC Class Cofactors. PLoS Biol 10: e1001351 doi:10.1371/journal.pbio.1001351.

45. SaadaouiM, MerabetS, Litim-MecheriI, ArbeilleE, SambraniN, et al. (2011) Selection of distinct Hox-Extradenticle interaction modes fine-tunes Hox protein activity. Proc Natl Acad Sci U S A 108: 2276–2281.

46. LelliKM, NoroB, MannRS (2011) Variable motif utilization in homeotic selector (Hox)-cofactor complex formation controls specificity. Proc Natl Acad Sci U S A 108: 21122–21127.

47. NoroB, LelliK, SunL, MannRS (2011) Competition for cofactor-dependent DNA binding underlies Hox phenotypic suppression. Genes Dev 25: 2327–2332.

48. TschoppP, ChristenAJ, DubouleD (2012) Bimodal control of Hoxd gene transcription in the spinal cord defines two regulatory subclusters. Development 139: 929–939.

49. GalantR, WalshCM, CarrollSB (2002) Hox repression of a target gene: extradenticle-independent, additive action through multiple monomer binding sites. Development 129: 3115–3126.

50. MisraM, SoursE, Lance-JonesC (2012) Hox transcription factors influence motoneuron identity through the integrated actions of both homeodomain and non-homeodomain regions. Dev Dyn 241: 718–731.

51. MerabetS, Litim-MecheriI, KarlssonD, DixitR, SaadaouiM, et al. (2011) Insights into Hox protein function from a large scale combinatorial analysis of protein domains. PLoS Genet 7: e1002302 doi:10.1371/journal.pgen.1002302.

52. TsuchidaT, EnsiniM, MortonSB, BaldassareM, EdlundT, et al. (1994) Topographic organization of embryonic motor neurons defined by expression of LIM homeobox genes. Cell 79: 957–970.