Limits...
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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Ectopic activation of spinal/hindbrain gene expression in Islet1 CKO sensory ganglia(A) Microarray analysis of E12.5 DRG reveals abnormal expression of transcription factors usually associated with spinal neuron development (Lhx1, Lhx2, Olig1, Olig2, Lbxcor1), and decreased expression of Islet2. LIM-interacting proteins of the Ldb and LMO families, which are normally expressed in both sensory ganglia and spinal cord, show relatively modest changes. Asterisks indicate significant increase or decrease (change p <0.002 or >0.998) in two concordant comparisons. (B) In situ hybridization shows expression of increased transcription factors increased in Islet1 CKO embryos in the spinal cord and DRG. Islet1 CKO views are shown at higher magnification to reveal detail. (C) Concordant abnormal expression of CNS transcription factors in the E12.5 trigeminal ganglia. DRG, dorsal root ganglion; HB, hindbrain; SC, spinal cord; TG, trigeminal ganglion. Scale: B, 100µm; C, 200µm.
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Figure 5: Ectopic activation of spinal/hindbrain gene expression in Islet1 CKO sensory ganglia(A) Microarray analysis of E12.5 DRG reveals abnormal expression of transcription factors usually associated with spinal neuron development (Lhx1, Lhx2, Olig1, Olig2, Lbxcor1), and decreased expression of Islet2. LIM-interacting proteins of the Ldb and LMO families, which are normally expressed in both sensory ganglia and spinal cord, show relatively modest changes. Asterisks indicate significant increase or decrease (change p <0.002 or >0.998) in two concordant comparisons. (B) In situ hybridization shows expression of increased transcription factors increased in Islet1 CKO embryos in the spinal cord and DRG. Islet1 CKO views are shown at higher magnification to reveal detail. (C) Concordant abnormal expression of CNS transcription factors in the E12.5 trigeminal ganglia. DRG, dorsal root ganglion; HB, hindbrain; SC, spinal cord; TG, trigeminal ganglion. Scale: B, 100µm; C, 200µm.

Mentions: We also identified a second class of increased transcripts which are not normally expressed in the sensory ganglia at any phase of development (Fig. 5). These genes include the LIM-homeodomain factors Lhx1 (Lim1) and Lhx2 (LH2A), the transcriptional co-regulator Lbxcor1, and the bHLH factors Olig1 and Olig2. Although these factors are not expressed in the DRG, each has a known role in spinal cord development (Discussion). The transcription factor Tcafp2b (Ap2β, Fig. 5B) has characteristics of both classes of increased transcripts, in that it is normally expressed in early sensory development as are the bHLH genes, and is also expressed in postmitotic spinal neurons at E12.5. Lbxcor1 and Tcafp2b were strongly expressed only in a subset of DRG neurons in CKO embryos (Fig. 5B, enlarged views), perhaps owing to the activity of redundant repressive factors in the neurons which do not upregulate these genes.


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)

Ectopic activation of spinal/hindbrain gene expression in Islet1 CKO sensory ganglia(A) Microarray analysis of E12.5 DRG reveals abnormal expression of transcription factors usually associated with spinal neuron development (Lhx1, Lhx2, Olig1, Olig2, Lbxcor1), and decreased expression of Islet2. LIM-interacting proteins of the Ldb and LMO families, which are normally expressed in both sensory ganglia and spinal cord, show relatively modest changes. Asterisks indicate significant increase or decrease (change p <0.002 or >0.998) in two concordant comparisons. (B) In situ hybridization shows expression of increased transcription factors increased in Islet1 CKO embryos in the spinal cord and DRG. Islet1 CKO views are shown at higher magnification to reveal detail. (C) Concordant abnormal expression of CNS transcription factors in the E12.5 trigeminal ganglia. DRG, dorsal root ganglion; HB, hindbrain; SC, spinal cord; TG, trigeminal ganglion. Scale: B, 100µm; C, 200µm.
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Figure 5: Ectopic activation of spinal/hindbrain gene expression in Islet1 CKO sensory ganglia(A) Microarray analysis of E12.5 DRG reveals abnormal expression of transcription factors usually associated with spinal neuron development (Lhx1, Lhx2, Olig1, Olig2, Lbxcor1), and decreased expression of Islet2. LIM-interacting proteins of the Ldb and LMO families, which are normally expressed in both sensory ganglia and spinal cord, show relatively modest changes. Asterisks indicate significant increase or decrease (change p <0.002 or >0.998) in two concordant comparisons. (B) In situ hybridization shows expression of increased transcription factors increased in Islet1 CKO embryos in the spinal cord and DRG. Islet1 CKO views are shown at higher magnification to reveal detail. (C) Concordant abnormal expression of CNS transcription factors in the E12.5 trigeminal ganglia. DRG, dorsal root ganglion; HB, hindbrain; SC, spinal cord; TG, trigeminal ganglion. Scale: B, 100µm; C, 200µm.
Mentions: We also identified a second class of increased transcripts which are not normally expressed in the sensory ganglia at any phase of development (Fig. 5). These genes include the LIM-homeodomain factors Lhx1 (Lim1) and Lhx2 (LH2A), the transcriptional co-regulator Lbxcor1, and the bHLH factors Olig1 and Olig2. Although these factors are not expressed in the DRG, each has a known role in spinal cord development (Discussion). The transcription factor Tcafp2b (Ap2β, Fig. 5B) has characteristics of both classes of increased transcripts, in that it is normally expressed in early sensory development as are the bHLH genes, and is also expressed in postmitotic spinal neurons at E12.5. Lbxcor1 and Tcafp2b were strongly expressed only in a subset of DRG neurons in CKO embryos (Fig. 5B, enlarged views), perhaps owing to the activity of redundant repressive factors in the neurons which do not upregulate these genes.

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