RT Journal Article
SR Electronic
T1 Gli3 loss-of-function compromises vomeronasal neurogenesis, formation of olfactory ensheathing cells in the nasal mucosa, and GnRH-1 neuronal migration
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 643155
DO 10.1101/643155
A1 Ed Zandro M. Taroc
A1 Ankana Naik
A1 Jennifer M Lin
A1 Nicolas B Peterson
A1 David Keefe
A1 Elizabet Genis
A1 Gabriele Fuchs
A1 Ravikumar Balasubramanian
A1 Paolo E. Forni
YR 2019
UL http://biorxiv.org/content/early/2019/05/20/643155.abstract
AB Gonadotropin-releasing-hormone-1 neurons (GnRH-1ns) control pubertal onset, and fertility. During mammalian development, GnRH-1ns migrate from the developing vomeronasal organ (VNO) into the brain, where they control the pituitary release of gonadotropins. Loss-of-function of the transcription factor Gli3 disrupts olfactory development, however, if Gli3 plays roles in GnRH-1 neuronal development is unclear. By analyzing Gli3 extra-toe mutants (Gli3Xt/Xt), we found neurogenic defects in the VNO, lack of olfactory ensheathing cells in the nasal mucosa and disrupted GnRH-1 neuronal migration. We discovered that Gli3 loss-of-function impairs the formation of achaete-scute family bHLH transcription factor 1 (Ascl-1) positive vomeronasal progenitors, but not the onset of GnRH-1ns. Moreover, the dysmorphic brain of Gli3Xt/Xt mutants also displayed altered Semaphorin-3A expression, a key guidance cue for GnRH-1 migration. In contrast to Gli3Xt/Xt, Ascl-1null mutants showed reduced neurogenesis for both vomeronasal and GnRH-1ns. The non-overlapping phenotype between Gli3Xt/Xt and Ascl-1null mutants suggests that Ascl-1 is crucial for GnRH-1 progenitors but, in these cells, independent of Gli3 control. Since Kallmann syndrome (KS) shows defects in GnRH migration, we examined KS patient samples using whole exome sequencing. We identified and validated a new GLI3 loss-of-function variant. Our data suggest that GLI3 is a candidate modifier gene contributing to KS etiology.