Transcript Hoxd1

Summary so far …….
Somatosensory system > sense of body & environment on body
> sensory modalities: touch, pain, temperature; proprioception
> somatosensation integrated into spinal circuits > reflexes
> somatosensory information sent to somatosensory cortex
Development
PNS nervous system > neural crest derived > somatosensory neurons of the DRG
> specialized for sensory modalities
The sense of touch
Importance of touch > neural crest derived > somatosensory neurons of the DRG
> specialized for touch
> Transcription factors driave differentiation
of touch sensing neurons (cMaf; MafA)
Species-specific neuronal circuits directed by neurotrophic factor
control of transcriptional programmes
> novel neural circuits arise during evolution to encode unique
behaviors among different animal species.
How did somatosensory system evolve?
What adaptations have been necessary in vertebrates?
- Constant temperature (sea) > variable temperature (land)
- Fins became limbs (circuits for coordinated movement)
- Scales (fish), feathers (birds) & skin (mammals)
Chick
Mouse
> hopping gait = sautiller
> alternating locomotion
> feathers
> hairs, a cold adaptation necessary
for the prevention of heat loss.
Expect species specific differences in spinal circuitry
Different innervation of skin in mammals and birds
elaborate nerve endings
in the epidermis
no nerve endings
in the epidermis
Diversité des neurones sensoriels périphériques
des ganglions rachidiens
Ganglion Rachidien Dorsaux (DRG)
TrkA ou c-Ret
TrkC
TrkB et/ou c-Ret
Moelle épinière
Neurones prorioceptifs
Neurones mécanoceptifs
Neurones nociceptifs & thermosensitifs
Marmigère and Ernfors Nature Reviews Neuroscience 8, 114–127 (February 2007)
Thermonociception
Mechanoception
Proprioception
Somatosensory neurons are highly diverse
Spinal cord
Dorsal root ganglion (DRG)
Proprioceptors
Mechanoreceptors
TrkC/NT-3
TrkB/BDNF
Nociceptors
Thermoceptors
TrkA/NGF
Ret/GDNF
Neurotrophins and sensory
neuron development
> survival
> maturation
> axonal projections
Intrinsic versus extrinsic signals for neuronal differentiation
Concept:
Intrinsic & extrinsic signals co-ordinate sensory neuron – spinal neuron interactions
Da Silva & Wang 2010 Curr. Op. Neurobiol
Intrinsic versus extrinsic signals for neuronal differentiation
Figure 2. Peripheral signals control the formation of dorsal root ganglion sensory and motor neuron projections. (a,b) Subpopulations
of brachial motor neurons extend their axons towards their target muscles. En route, they encounter glial-cell-line-derived ne...
Simon Hippenmeyer, Ina Kramer, Silvia Arber
Control of neuronal phenotype: what targets tell the cell bodies
Concept:
A species-specific signal controls nociceptive circuit formation
NGF
TrkA
HoxD1
Skin
Nociceptive
neuron
Spinal cord
neuron
DRG
Spinal cord
Summary
The form of a scientific paper
Hypothesis
Species are endowed with unique sensory capabilities encoded by divergent neural circuits.
One potential explanation for how divergent circuits have evolved is that conserved
extrinsic signals are differentially interpreted by developing neurons of different species
to yield unique patterns of axonal connections. Although NGF controls survival, maturation
and axonal projections of nociceptors of different vertebrates, whether the NGF signal is
differentially transduced in different species to yield unique features of nociceptor circuits
is unclear.
Results
We identified a species-specific signaling module induced by NGF and mediated by a
rapidly evolving Hox transcription factor, Hoxd1. Mice lacking Hoxd1 display altered
nociceptor circuitry which resembles that normally found in chicks. Conversely, ectopic
expression of Hoxd1 in developing chick nociceptors promotes a pattern of axonal
projections reminiscent of the mouse.
Conclusion
We propose that conserved growth factors control divergent neuronal transcriptional
events which mediate interspecies differences in neural circuits and the behaviors
they control.
NGF and sensory
neuron development
Nociceptors
- pain
- temperature
- touch
- itch
> survival
> maturation
> axonal projections
Hox genes in development
Hox genes pattern the rostro-caudal axis
Hox genes pattern the rostro-caudal axis
HoxD family – role in limb patterning (medio-lateral axis)
1. Search for transcriptional targets of NGF different between birds and mammals
i. Genes enriched in nociceptors
ii. NGF-regulated genes expressed in nociceptors in vivo
iii. mouse DRG explants grown in the presence or absence of NGF for identification
of NGF-dependent genes expressed in nociceptors in vitro.
> NGF dependent genes in mouse nociceptors
Mouse DRG culture
+ NGF
Chick DRG culture
+ NGF
> differentially regulated genes detected by Q-PCR
HoxD1
Results
1. A screen for genes controlled by NGF signalling in mammalian nociceptors
HoxD1 is an NGF regulated in mouse, but not in chick
Fig. 1
HoxD1 expressed in mouse nociceptors (TrkA+), but not in chick
2. Developmental expression of Hoxd1 in different vertebrate species
> HoxD1/TrkA co-expression is specific to mouse
2. Developmental expression of Hoxd1 in different vertebrate species
WT
HoxD1 -/-
Nociceptive innervation of the skin of Hoxd1−/− mice resembles that of non-mammalian
vertebrates e.g. birds (in B loss of circular endings around hair follicles)
Abnormal expression of
Mrgbp4 in peptidergic neurons
in HoxD1-/- mice
3. Hoxd1 instructs nociceptor central axonal projections within the mammalian spinal cord
Mirroring species-specific differences in innervation of the skin, the patterns of nociceptive
axonal projections within the spinal cords of mammals and birds are also distinct
> ectopic innervation of deep layers of the spinal cord
Different patterns of nociceptor innervation of the spinal cord in mouse and chick
4. Hoxd1 instructs nociceptor central axonal projections within the mammalian spinal cord
- suggests that Hoxd1 mediates NGF-dependent suppression of nociceptor projections
into deep layers of the spinal cord.
In Mouse
Loss of NGF
or
Loss of HoxD1
> “chick-type” skin & spinal cord innervation
What is effect of expressing HoxD1 in chick DRG neurons?
The gain-of-function experiment
Electroporation of plasmid DNA into chick embryo neural tube
Negatively charged DNA moves towards the anode
Chick as a model for study of spinal cord circuitry
5. Ectopic Hoxd1 expression in chick nociceptors induces mammal-like traits
> HoxD1 expression in chick suppressed deep layer nociceptor innervation in chick
HoxD1 mutation changes nociceptor circuitry
in the mouse spinal cord
Physiological consequences?
6. Hoxd1−/− mice have deficits in cold sensitivity
Conclusion
> Hoxd1 instructs development of mammal-specific features of nociceptive
neural circuitry.
> behavioral sensitivity to extreme cold is markedly compromised
in Hoxd1 mutant mice
> suggests HoxD1 was co-opted by nociceptors in mammals for cold sensation
The end