InDRG11Knock-Out Mice, Trigeminal Cell Death Is Extensive and Does Not Account for Failed Brainstem Patterning

Abstract

A previous study (Ding et al., 2003) showed that the homeodomain transcription factor DRG11 is necessary for pattern formation in the trigeminal nucleus principalis (PrV), the requisite brainstem nucleus for development of the whisker-to-barrel cortex pathway. However, it is not known how DRG11 contributes to pattern formation. Anatomical studies were performed in DRG11 knock-out (Ϫ/Ϫ) and DRG11/Bax double Ϫ/Ϫ mice to test the hypotheses that DRG11 is required for neuronal survival in the V pathway and that PrV cell death is sufficient to explain pattern alterations. At birth, DRG11 Ϫ/Ϫ mice had equivalent cell loss in the V ganglion, PrV, and spinal V subnucleus interpolaris (SpVi). Because whisker-related patterns were normal in the SpVi, cell death would not appear to explain failed pattern formation in the mutant PrV. Electron microscopy revealed exuberant apoptosis and necrosis as the mechanisms of PrV cell death occurring in the late prenatal and newborn DRG11 Ϫ/Ϫ , when such cell death was up to six times more prevalent than normal.

Abolition of lemniscal barrellette patterning in Prrxl1 knockout mice: Effects upon ingestive behavior

“…Additionally, the overall size of PrV and SpVi appear to be smaller in the KO animal. While this might be attributed to the increased cell death observed in both PrV (Ding et al 2003) and SpVi (Jacquin et al 2008), cell death is not the cause of the lost patterning, as demonstrated by a cross with Bax-expressing mice which curtailed the high levels of apoptosis but did not recover patterning deficits (Jacquin et al 2008). We therefore suggest that cell death is also not the cause of the functional deficits observed in our Prrxl1 animals, although further study using Bax-crossed animals would have utility.…”

“…Prrxl1 (previously named DRG11) is required for patterning of nociceptive circuitry in the dorsal spinal cord (Saito et al 1995;Chen et al 2001). Its deletion also disrupts the normal development of patterning in the lemniscal system, abolishing whiskerrelated barrellettes in the lemniscal brainstem nucleus (PrV) while leaving them intact in the paralemniscal brainstem nucleus (SpVi) (Wang et al 2007;Jacquin et al 2008). Thus Prrxl1 deletion, by disrupting pattern formation in the lemniscal, but not the paralemniscal trigeminal pathway, provides an opportunity to dissociate the functions of the two pathways in trigeminally mediated behaviors.…”

Whisker-related circuitry in the trigeminal nucleus principalis: Topographic precision

“…A number of convenient methods can be used to reveal this topographic pattern, including Nissl and cytochrome oxidase staining. The ease with which this robust pattern is revealed, the accessibility of the whiskers for experimental manipulations, and the prominence of barrels in transgenic mice make the whisker-barrel model a favored model for revealing mechanisms of central nervous system (CNS) information processing, development, and plasticity (reviewed by Jones and Diamond 1995;Erzurumlu et al 2006;Jacquin et al 2008).…”

Whisker-related circuitry in the trigeminal nucleus principalis: Ultrastructure

“…Such patterns emerge sequentially and centripetally over a prolonged period spanning preand postnatal development, and orderly peripheral projections of V ganglion cells are required for the development of these patterns (e.g., Killackey et al 1990;Rhoades et al 1990;Henderson and Jacquin 1995). Whereas molecular mechanisms subserving pattern formation in this system are now the subject of much attention (e.g., Ding et al 2003;Erzurumlu et al 2006;Jacquin et al 2008;Xiang et al 2010;Mosconi et al 2013), an actual patterning mechanism has yet to be revealed. What is known is that the PrV must be intact for whisker patterns to form in the thalamus and cerebral cortex (Killackey and Fleming 1985), whereas the SpV nucleus is not required, nor sufficient, for higher order pattern formation.…”