The Runx3 transcription factor regulates development and survival of TrkC dorsal root ganglia neurons.
The RUNX transcription factors are important regulators of linage-specific gene expression in major developmental pathways. Recently, we demonstrated that Runx3 is highly expressed in developing cranial and dorsal root ganglia (DRGs). Here we report that within the DRGs, Runx3 is specifically expressed in a subset of neurons, the tyrosine kinase receptor C (TrkC) proprioceptive neurons. We show that Runx3-deficient mice develop severe limb ataxia due to disruption of monosynaptic connectivity between intra spinal afferents and motoneurons. We demonstrate that the underlying cause of the defect is a loss of DRG proprioceptive neurons, reflected by a decreased number of TrkC-, parvalbumin- and beta-galactosidase-positive cells. Thus, Runx3 is a neurogenic TrkC neuron-specific transcription factor. In its absence, TrkC neurons in the DRG do not survive long enough to extend their axons toward target cells, resulting in lack of connectivity and ataxia. The data provide new genetic insights into the neurogenesis of DRGs and may help elucidate the molecular mechanisms underlying somatosensory-related ataxia in humans.
Levanon
Ditsa
D
Department of Molecular Genetics, The Weizmann Institute of Science, Rehovot 76100, Israel.
Bettoun
David
D
Harris-Cerruti
Catherine
C
Woolf
Eilon
E
Negreanu
Varda
V
Eilam
Raya
R
Bernstein
Yael
Y
Goldenberg
Dalia
D
Xiao
Cuiying
C
Fliegauf
Manfred
M
Kremer
Eitan
E
Otto
Florian
F
Brenner
Ori
O
Lev-Tov
Aharon
A
Groner
Yoram
Y
D000344:Afferent Pathways / Q000503:physiopathology; D000818:Animals; D001259:Ataxia / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D001369:Axons / Q000648:ultrastructure; D015415:Biomarkers; D016923:Cell Death; D050677:Core Binding Factor Alpha 3 Subunit; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D005727:Ganglia, Spinal / Q000737:chemistry / Q000473:pathology*; D018507:Gene Expression Regulation, Developmental; D005838:Genotype; D051379:Mice; D008813:Mice, Inbred ICR; D018345:Mice, Knockout; D008818:Mice, Neurologic Mutants; D009046:Motor Neurons / Q000502:physiology; D009470:Muscle Spindles / Q000473:pathology; D009419:Nerve Tissue Proteins / Q000032:analysis / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D009475:Neurons, Afferent / Q000166:cytology*; D010320:Parvalbumins / Q000032:analysis; D011434:Proprioception / Q000235:genetics / Q000502:physiology*; D020812:Receptor, trkC / Q000032:analysis*; D020886:Somatosensory Disorders / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D013116:Spinal Cord / Q000473:pathology; D013569:Synapses / Q000473:pathology; D009435:Synaptic Transmission; D014157:Transcription Factors / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D012668:Trigeminal Ganglion / Q000737:chemistry / Q000473:pathology; D001616:beta-Galactosidase / Q000032:analysis
D015415:Biomarkers; D050677:Core Binding Factor Alpha 3 Subunit; D004268:DNA-Binding Proteins; D009419:Nerve Tissue Proteins; D010320:Parvalbumins; C493730:Runx3 protein, mouse; D014157:Transcription Factors; D020812:Receptor, trkC; D001616:beta-Galactosidase