The LIM-Homeodomain transcription factor Islet-1 is required for the development of sympathetic neurons and adrenal chromaffin cells

Abstract

Islet-1 is a LIM-Homeodomain transcription factor with important functions for the development of distinct neuronal and non-neuronal cell populations. We show here that Islet-1 acts genetically downstream of Phox2B in cells of the sympathoadrenal cell lineage and that the development of sympathetic neurons and chromaffin cells is impaired in mouse embryos with a conditional deletion of Islet-1 controlled by the wnt1 promotor. Islet-1 is not essential for the initial differentiation of sympathoadrenal cells, as indicated by the correct expression of pan-neuronal and catecholaminergic subtype specific genes in primary sympathetic ganglia of Islet-1 deficient mouse embryos. However, our data indicate that the subsequent survival of sympathetic neuron precursors and their differentiation towards TrkA expressing neurons depends on Islet-1 function. In contrast to spinal sensory neurons, sympathetic neurons of Islet-1 deficient mice did not display ectopic expression of genes normally present in the CNS. In Islet-1 deficient mouse embryos the numbers of chromaffin cells were only mildly reduced, in contrast to that of sympathetic neurons, but the initiation of the adrenaline synthesizing enzyme PNMT was abrogated and the expression level of chromogranin A was diminished. Microarray analysis revealed that developing chromaffin cells of Islet-1 deficient mice displayed normal expression levels of TH, DBH and the transcription factors Phox2B, Mash-1, Hand2, Gata3 and Insm1, but the expression levels of the transcription factors Gata2 and Hand1, and AP-2β were significantly reduced. Together our data indicate that Islet-1 is not essentially required for the initial differentiation of sympathoadrenal cells, but has an important function for the correct subsequent development of sympathetic neurons and chromaffin cells.

Human axial progenitors generate trunk neural crest cells in vitro

“…FOXC1 and 2 ( Seo and Kume, 2006 ); PDGFRa ( Tallquist and Soriano, 2003 ); TBX2/3 [ Mesbah et al, 2012 ]) and vagal/enteric NC markers ( PHOX2A ( Young et al, 1999 ); KITLG ( Torihashi et al, 1996 ); ARPC1B ( Iwashita et al, 2003 ) ( Figure 4E ). In contrast, known trunk NC, sympathoadrenal and sympathetic/sensory neuron regulators such as CDX2 ( Sanchez-Ferras et al, 2016 ), INSM1 ( Wildner et al, 2008 ), NEUROG1 ( Perez et al, 1999 ) ( Figure 4F ) and ISL1 ( Huber et al, 2013 ) ( Supplementary file 2 ) were induced only in NC cells derived from axial progenitors. We also identified ASLX3 , the human homologue of the Drosophila polycomb protein asx ( Katoh and Katoh, 2004 ) which has been recently linked to the developmental syndrome Bainbridge-Ropers ( Bainbridge et al, 2013 ) as a novel trunk NC marker ( Figure 4F , Supplementary file 2 ).…”

Human axial progenitors generate trunk neural crest cells

“…FOXC1 and 2 (59); PDGFRa (60); TBX2/3 (61)) and vagal/enteric NC markers ( PHOX2A (62); KITLG (63); ARPC1B (64) ( Figure 4E) . In contrast, known trunk NC, sympathoadrenal and sympathetic/sensory neuron regulators such as CDX2 (47), INSM1 (65), ISL1 (66) and NEUROG1 (67) were induced only in NC cells derived from axial progenitors ( Figure 4F , Table S2 ). We also identified ASLX3 , the human homologue of the Drosophila polycomb protein asx (68) which has been recently linked to the developmental syndrome Bainbridge-Ropers (69) as a novel trunk NC marker ( Figure 4F , Table S2 ).…”

Motoneurons regulate the central pattern generator during drug-induced locomotor-like activity in the neonatal mouse

“…To obtain additional evidence that the light-induced changes in frequency and phase were due to changes in the firing of motoneurons rather than some other neuronal class, we repeated the experiments in cords in which Arch was expressed in Isl1 + neurons. Isl1 is expressed in primary afferents, dI3 interneurons, motoneurons, and sympathetic motoneurons ( Figure 7A1-3 ; Tsuchida et al, 1994 ; Pfaff et al, 1996 ; Bui et al, 2013 ; Huber et al, 2013 ). We hypothesized that if light-induced changes in motoneuron firing regulate the decreased locomotor frequency in the ChAT-Arch cords then we should observe similar effects in the Isl1 -Arch cords.…”