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

Abstract

We have 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 are grossly normal in the absence of Islet1. However, from E12.5 onward, Islet1 mutant embryos exhibit loss of the nociceptive markers TrkA and Runx1 and a near absence of cutaneous innervation. Proprioceptive neurons characterized by the expression of TrkC/Runx3/Etv1 are relatively spared. Microarray analysis of Islet1 mutant ganglia reveals prolonged expression of developmental regulators normally restricted to early sensory neurogenesis, and ectopic expression of transcription factors normally found in the CNS but not in sensory ganglia. Later excision of Islet1 does not reactivate early genes, but results 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.

Islet1 selectively promotes peripheral axon outgrowth in Rohon‐Beard primary sensory neurons

“…These finding suggest that Isl1 regulates not only the expression of dpysl3 but also some other unknown molecules that are involved in the regulation of axonal outgrowth of RB neurons. This is consistent with a previous expression profiling analysis of DRG neurons in isl1 CKO mice (Sun et al, 2008). This study demonstrates that Isl1 represses or enhances various types of genes that are involved in early neurogenesis, cell survival, and specific nociceptor linage.…”

“…These results were different from those of previous studies that showed that the expression of isl2a was reduced in both primary motor neurons and RB neurons in the isl1 morphants (Hutchinson and Eisen, 2006). Expression profile analysis of dorsal root ganglion (DRG) in isl1 CKO mice demonstrated that in the early developmental stage (E12.5), loss of function of isl1 reduces isl2 expression, while in the late developmental stage (E14.5), isl2 expression was recovered (Sun et al, 2008). This result demonstrates that the early expression of isl2 is regulated by Isl1 while its late expression is independent from Isl1 regulation (Sun et al, 2008).…”

“…Expression profile analysis of dorsal root ganglion (DRG) in isl1 CKO mice demonstrated that in the early developmental stage (E12.5), loss of function of isl1 reduces isl2 expression, while in the late developmental stage (E14.5), isl2 expression was recovered (Sun et al, 2008). This result demonstrates that the early expression of isl2 is regulated by Isl1 while its late expression is independent from Isl1 regulation (Sun et al, 2008). Based on these studies, we believe that in zebrafish, as in mouse, the expression of isl2a may be regulated by 2 machineries: Isl1 dependent and Isl1 independent.…”

“…Isl1 is expressed in motor and retinal neurons of the central nervous system (CNS) and in various types of sensory neurons, including neurons of the dorsal root and cranial ganglia (Appel et al, 1995;Elshatory et al, 2007;Hutchinson and Eisen, 2006;Pfaff et al, 1996;Sun et al, 2008;Thaler et al, 2002Thaler et al, , 2004Tsuchida et al, 1994;Uemura et al, 2005). In mice, isl1-deficient embryos die before sensory neuron maturation (Pfaff et al, 1996).…”

“…In mice, isl1-deficient embryos die before sensory neuron maturation (Pfaff et al, 1996). On the other hand, isl1 conditional knockout (CKO) mice, which avoid early embryonic death, show defects in sensory innervation to the CNS and periphery (Sun et al, 2008). In invertebrates, loss of function of islet, the Drosophila orthologue of vertebrate isl1, causes abnormal axonal pathfinding and loss of neurotransmitter synthesis in motor and interneurons (Thor and Thomas, 1997).…”