Loss of Hoxb8 alters spinal dorsal laminae and sensory responses in mice

Abstract

Although Hox gene expression has been linked to motoneuron identity, a role of these genes in development of the spinal sensory system remained undocumented. Hoxb genes are expressed at high levels in the dorsal horn of the spinal cord. Hoxb8 null mutants manifest a striking phenotype of excessive grooming and hairless lesions on the lower back. Applying local anesthesia underneath the hairless skin suppressed excessive grooming, indicating that this behavior depends on peripheral nerve activity. Functional ablation of mouse Hoxb8 also leads to attenuated response to nociceptive and thermal stimuli. Although spinal ganglia were normal, a lower postmitotic neural count was found in the dorsalmost laminae at lumbar levels around birth, leading to a smaller dorsal horn and a correspondingly narrowed projection field of nociceptive and thermoceptive afferents. The distribution of the dorsal neuronal cell types that we assayed, including neurons expressing the itch-specific gastrin-releasing peptide receptor, was disorganized in the lumbar region of the mutant. BrdU labeling experiments and gene-expression studies at stages around the birth of these neurons suggest that loss of Hoxb8 starts impairing development of the upper laminae of the lumbar spinal cord at approximately embryonic day (E)15.5. Because none of the neuronal markers used was unexpressed in the adult dorsal horn, absence of Hoxb8 does not impair neuronal differentiation. The data therefore suggest that a lower number of neurons in the upper spinal laminae and neuronal disorganization in the dorsal horn underlie the sensory defects including the excessive grooming of the Hoxb8 mutant.anteroposterior patterning ͉ mouse Hox genes ͉ spinal cord ͉ reaction to heat pain and itch

Hox Genes: Choreographers in Neural Development, Architects of Circuit Organization

“…Serotonergic neuron generation also relies on Hox-dependent programs (Pattyn et al, 2003) while Hox2 paralog genes control oligodendrocyte production (Miguez et al, 2012). At spinal levels, Hoxb8 has been implicated in the organization of dorsal horn neurons that relay nociceptive stimuli at lumbar levels, survival of the second spinal ganglion and the specification of noradrenergic sympathetic neurons of the autonomic nervous system (Holstege et al, 2008; Huber et al, 2012; van den Akker et al, 1999) while Hoxb13 acts to define the caudal boundary of the spinal cord (Economides et al, 2003). …”

Rodent models of obsessive compulsive disorder: Evaluating validity to interpret emerging neurobiology

“…HoxB8 -null animals self-groom excessively and also have increased social grooming of control animals. A subsequent report from another group using a different Hoxb8 null mouse line suggested that deficits in spinal cord function led to changes in sensitivity to pain, potentially underlying the excessive, self-injurious grooming behavior (Holstege et al, 2008). A follow-up study conducted by the Capecchi group in the original Hoxb8 null mice, however, clearly demonstrated that central nervous system function was responsible for excessive grooming in these animals (Chen et al, 2010).…”

Physiological Roles of Group X-secreted Phospholipase A2 in Reproduction, Gastrointestinal Phospholipid Digestion, and Neuronal Function

“…For instance, gene manipulation of Hoxb8, a homeobox-containing transcription factor, resulted in abnormalities in the obsessivecompulsive disorder circuit in the central nervous system, ontogenesis, and development of the upper cervical DRG and the nociceptive response (73)(74)(75). Kifc2 is a neuron-specific C-terminal kinesin superfamily motor for the transport of multivesicular body-like organelles in dendrites (76).…”