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A central role for Islet1 in sensory neuron development linking sensory and spinal gene regulatory programs.

Sun Y, Dykes IM, Liang X, Eng SR, Evans SM, Turner EE - Nat. Neurosci. (2008)

Bottom Line: Microarray analysis of Isl1 mutant ganglia revealed prolonged expression of developmental regulators that are normally restricted to early sensory neurogenesis and ectopic expression of transcription factors that are normally found in the CNS, but not in sensory ganglia.Later excision of Isl1 did not reactivate early genes, but resulted in decreased expression of transcripts related to specific sensory functions.Together these results establish a central role for Islet1 in the transition from sensory neurogenesis to subtype specification.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, University of California San Diego, La Jolla, California 93093, USA.

ABSTRACT
We used conditional knockout strategies in mice to determine the developmental events and gene expression program regulated by the LIM-homeodomain factor Islet1 in developing sensory neurons. Early development of the trigeminal and dorsal root ganglia was grossly normal in the absence of Islet1. From E12.5 onward, however, Isl1 mutant embryos showed a loss of the nociceptive markers TrkA and Runx1 and a near absence of cutaneous innervation. Proprioceptive neurons characterized by the expression of TrkC, Runx3 and Etv1 were relatively spared. Microarray analysis of Isl1 mutant ganglia revealed prolonged expression of developmental regulators that are normally restricted to early sensory neurogenesis and ectopic expression of transcription factors that are normally found in the CNS, but not in sensory ganglia. Later excision of Isl1 did not reactivate early genes, but resulted in decreased expression of transcripts related to specific sensory functions. Together these results establish a central role for Islet1 in the transition from sensory neurogenesis to subtype specification.

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Expression of transcription factors regulating sensory subtype specification is altered in the DRG of Islet1 CKO embryos(A,B) Runx1 expression in the brachial level DRG at E12.5 and E14.5, showing markedly diminished expression in CKO ganglia. (C,D). Runx1, Ret and TrkA expression in P1 DRG. Subsets of neurons expressing all combinations of these markers appear markedly diminished in CKO DRG. (E–G) Runx3 and Islet1 expression in the DRG of control and CKO embryos at E11.5. In control embryos, Runx3 immunoreactive neurons are a subset of Islet1+ cells. However, in the absence of Islet1, Runx3 expression is largely preserved. In G the number of Runx3 cells shows a modest decrease in CKO ganglia which did not reach statistical significance. (H,I) Runx3 and TrkC expression at E12.5 and E14.5. Neurons expressing these proprioceptive markers are relatively spared in Islet1 CKO ganglia, and account for an increasing fraction of the remaining DRG neurons as development progresses. (J,K) At E11.5, Islet1 is co-expressed with Etv1 in a subset of DRG neurons. At E14.5, Etv1+ neurons are relatively spared, and nearly all co-express TrkC, indicating that they are highly overlapping with the Runx3/TrkC population. (L) At 14.5, Islet1 is extensively co-expressed with Runx1 but is no longer co-expressed with Runx3 or Etv1. Mot, motor neurons; SC, spinal cord.
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Figure 3: Expression of transcription factors regulating sensory subtype specification is altered in the DRG of Islet1 CKO embryos(A,B) Runx1 expression in the brachial level DRG at E12.5 and E14.5, showing markedly diminished expression in CKO ganglia. (C,D). Runx1, Ret and TrkA expression in P1 DRG. Subsets of neurons expressing all combinations of these markers appear markedly diminished in CKO DRG. (E–G) Runx3 and Islet1 expression in the DRG of control and CKO embryos at E11.5. In control embryos, Runx3 immunoreactive neurons are a subset of Islet1+ cells. However, in the absence of Islet1, Runx3 expression is largely preserved. In G the number of Runx3 cells shows a modest decrease in CKO ganglia which did not reach statistical significance. (H,I) Runx3 and TrkC expression at E12.5 and E14.5. Neurons expressing these proprioceptive markers are relatively spared in Islet1 CKO ganglia, and account for an increasing fraction of the remaining DRG neurons as development progresses. (J,K) At E11.5, Islet1 is co-expressed with Etv1 in a subset of DRG neurons. At E14.5, Etv1+ neurons are relatively spared, and nearly all co-express TrkC, indicating that they are highly overlapping with the Runx3/TrkC population. (L) At 14.5, Islet1 is extensively co-expressed with Runx1 but is no longer co-expressed with Runx3 or Etv1. Mot, motor neurons; SC, spinal cord.

Mentions: Runx1 expression was detected beginning at E12.5 in control DRG, and was dramatically reduced in Islet1 CKO mice at all developmental stages examined (Fig. 3A–C). As expected from prior studies, at P1 control ganglia had substantial populations of both Runx1+/Ret+ and TrkA+/Ret+ neurons. In the DRG of Islet1 CKO embryos, both populations were markedly diminished, but the extent of co-expression of these markers was not affected (Fig. 3D).


A central role for Islet1 in sensory neuron development linking sensory and spinal gene regulatory programs.

Sun Y, Dykes IM, Liang X, Eng SR, Evans SM, Turner EE - Nat. Neurosci. (2008)

Expression of transcription factors regulating sensory subtype specification is altered in the DRG of Islet1 CKO embryos(A,B) Runx1 expression in the brachial level DRG at E12.5 and E14.5, showing markedly diminished expression in CKO ganglia. (C,D). Runx1, Ret and TrkA expression in P1 DRG. Subsets of neurons expressing all combinations of these markers appear markedly diminished in CKO DRG. (E–G) Runx3 and Islet1 expression in the DRG of control and CKO embryos at E11.5. In control embryos, Runx3 immunoreactive neurons are a subset of Islet1+ cells. However, in the absence of Islet1, Runx3 expression is largely preserved. In G the number of Runx3 cells shows a modest decrease in CKO ganglia which did not reach statistical significance. (H,I) Runx3 and TrkC expression at E12.5 and E14.5. Neurons expressing these proprioceptive markers are relatively spared in Islet1 CKO ganglia, and account for an increasing fraction of the remaining DRG neurons as development progresses. (J,K) At E11.5, Islet1 is co-expressed with Etv1 in a subset of DRG neurons. At E14.5, Etv1+ neurons are relatively spared, and nearly all co-express TrkC, indicating that they are highly overlapping with the Runx3/TrkC population. (L) At 14.5, Islet1 is extensively co-expressed with Runx1 but is no longer co-expressed with Runx3 or Etv1. Mot, motor neurons; SC, spinal cord.
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Related In: Results  -  Collection

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Figure 3: Expression of transcription factors regulating sensory subtype specification is altered in the DRG of Islet1 CKO embryos(A,B) Runx1 expression in the brachial level DRG at E12.5 and E14.5, showing markedly diminished expression in CKO ganglia. (C,D). Runx1, Ret and TrkA expression in P1 DRG. Subsets of neurons expressing all combinations of these markers appear markedly diminished in CKO DRG. (E–G) Runx3 and Islet1 expression in the DRG of control and CKO embryos at E11.5. In control embryos, Runx3 immunoreactive neurons are a subset of Islet1+ cells. However, in the absence of Islet1, Runx3 expression is largely preserved. In G the number of Runx3 cells shows a modest decrease in CKO ganglia which did not reach statistical significance. (H,I) Runx3 and TrkC expression at E12.5 and E14.5. Neurons expressing these proprioceptive markers are relatively spared in Islet1 CKO ganglia, and account for an increasing fraction of the remaining DRG neurons as development progresses. (J,K) At E11.5, Islet1 is co-expressed with Etv1 in a subset of DRG neurons. At E14.5, Etv1+ neurons are relatively spared, and nearly all co-express TrkC, indicating that they are highly overlapping with the Runx3/TrkC population. (L) At 14.5, Islet1 is extensively co-expressed with Runx1 but is no longer co-expressed with Runx3 or Etv1. Mot, motor neurons; SC, spinal cord.
Mentions: Runx1 expression was detected beginning at E12.5 in control DRG, and was dramatically reduced in Islet1 CKO mice at all developmental stages examined (Fig. 3A–C). As expected from prior studies, at P1 control ganglia had substantial populations of both Runx1+/Ret+ and TrkA+/Ret+ neurons. In the DRG of Islet1 CKO embryos, both populations were markedly diminished, but the extent of co-expression of these markers was not affected (Fig. 3D).

Bottom Line: Microarray analysis of Isl1 mutant ganglia revealed prolonged expression of developmental regulators that are normally restricted to early sensory neurogenesis and ectopic expression of transcription factors that are normally found in the CNS, but not in sensory ganglia.Later excision of Isl1 did not reactivate early genes, but resulted in decreased expression of transcripts related to specific sensory functions.Together these results establish a central role for Islet1 in the transition from sensory neurogenesis to subtype specification.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, University of California San Diego, La Jolla, California 93093, USA.

ABSTRACT
We used conditional knockout strategies in mice to determine the developmental events and gene expression program regulated by the LIM-homeodomain factor Islet1 in developing sensory neurons. Early development of the trigeminal and dorsal root ganglia was grossly normal in the absence of Islet1. From E12.5 onward, however, Isl1 mutant embryos showed a loss of the nociceptive markers TrkA and Runx1 and a near absence of cutaneous innervation. Proprioceptive neurons characterized by the expression of TrkC, Runx3 and Etv1 were relatively spared. Microarray analysis of Isl1 mutant ganglia revealed prolonged expression of developmental regulators that are normally restricted to early sensory neurogenesis and ectopic expression of transcription factors that are normally found in the CNS, but not in sensory ganglia. Later excision of Isl1 did not reactivate early genes, but resulted in decreased expression of transcripts related to specific sensory functions. Together these results establish a central role for Islet1 in the transition from sensory neurogenesis to subtype specification.

Show MeSH
Related in: MedlinePlus