UNSW Embryology

Molecular - Spinal Cord Axes

© Dr Mark Hill (2008)

Acknowledgements

Introduction

Spinal cord axes formation is cued from a number of external and internal patterning influences. Externally by specialized developmental structures, such as the notocord, and surrounding tissues, overlying ectoderm. Internally by segmental expression of homeobox genes, inductive influence of developing neural populations and their birth/migration pattern.

In general the spinal cord is laterally "symmetrical" with the antero-dorsally and rostro-caudally axes being different. The final cell population will include motor neurons, interneurons, glia as well as cellular processes extending from outside the segment (tracts).

 

 

 

The neural crest is not intrinsic part of spinal cord development though it is neural and in intimate contact with early spinal cord. Neural crest development and migration is covered in other notes. Neural crest neurons do though generate processes that contact both effector organs and spinal cord neurons.

 

Page Links: Introduction | Some Recent Findings | General_Axes | Ventral | Dorsal | Rostro-Caudal | Rostro-Caudal | Floorplate | Roofplate | References | Search PubMed | WWW Links | Glossary

Other Pages: Body Axes - Early | Body Axes - rostro/caudal | Body Axes - anterior/posterior | Body Axes - Left/Right | Limb Axes

Recent Findings

Zebrafish spinal cord - Bonner J, Gribble SL, Veien ES, Nikolaus OB, Weidinger G, Dorsky RI. Proliferation and patterning are mediated independently in the dorsal spinal cord downstream of canonical Wnt signaling. Dev Biol. 2008 Jan 1;313(1):398-407.

"Wnt signaling is required initially for proliferation throughout the entire spinal cord, and later for patterning dorsal progenitor domains. ...determine the transcriptional mediators of Wnt signaling that are responsible for patterning and proliferation."

Dorsal/Ventral - Alvarez-Medina R, Cayuso J, Okubo T, Takada S, Martí E. J. Wnt canonical pathway restricts graded Shh/Gli patterning activity through the regulation of Gli3 expression. Development. 2008 Jan;135(2):237-47.

"...we show that Wnt1/Wnt3a, by signalling through the canonical beta-catenin/Tcf pathway, control expression of dorsal genes and suppression of the ventral programme, and that this role in DV patterning depends on Gli activity. ...Gli3, by acting as a transcriptional repressor, restricted graded Shh/Gli ventral activity to properly pattern the spinal cord."

General Axes

 

 

Ventral

Patterning identified by experimental manipulation of tissue interactions. Initial experiments looked at how isolated tissues may influence the development of the spinal cord.

Repositionining the relative position of specific tissues both in vivo and in vitro. Then looking for specific markers, or alteration, of differentiation. These experimental results showed: notocord induced spinal tube formation, notocord induced floorplate formation, floorplate induced ventral spinal cord (motorneurons) and posterior ectoderm induced dorsal spinal cord (interneurons).

 

Later experiments identified the molecular mechanisms involved in the ventral signalling were mediated by the Shh/Gli signaling pathway.

(Image: Placzek M, Briscoe J., 2005)

Floorplate

Key organiser of the neural tube through initial induction by the notocord and then signaling through its own signal transduction pathway invloving: sonic hedghog (SHH) and forkhead box A2 (FOXA2), GLI activator (GLIA) and homologue of Drosophila MAD protein (SMAD).

(Image: Placzek M, Briscoe J., 2005)

Dorsal

Recent studies using a zebrafish model have identified the importance of WNT signaling in dorsal patterning of the spinal cord (Bonner J, etal., 2008). In particular, Wnt1/Wnt3a by signalling through the canonical beta-catenin/Tcf pathway (Alvarez-Medina R, etal., 2008). (More? Factor - Wnt7a)

Earlier studies in the frog identified growth factor controls patterning in embryonic mesoderm (TGFb). The related protein in flies determines dorsoventral homology search of vertebrate library identified protein of same family, dorsalin-1 (dsl-1) Basler et al., Cell 73 , p687, (1993).

Dorsalin-1 - naming comes from the obvious reason that it promotes the differentiation of neural crest cells. Also signal for dorsal signal of neural tube. Inhibits the differentiation of motoneurons. The implication is that dsl-1 and shh act antagonistically, or competitively to establish d-v axis of neural tube.

Roofplate

The roof plate is the region of the developing neural tube that occupies the dorsal midline along the entire anterior-posterior axis and is key to regulating dorsal signaling. Regulation is through factors produced and secreted that belong to the Bmp and Wnt families.

Roof plate signaling in developing spinal cord of mouse and chick embryos wild type and Wnt knockout. Roof plate (RP, red), Math1 (Cath1)-expressing domain (yellow), Ngn1/2-expressing domain (green), Mash1 (Cash1)-expressing domain (blue) and 6 classes of dorsal interneurons (dI1–6) are shown. Simultaneous loss of Wnt1/Wnt3a does not affect roof plate development in the mouse but causes severe reduction of Math1 and Ngn1/2-expressing domains accompanied by partial loss of dI1–3 interneurons. The Mash1-expressing domain and dI4–6 interneurons are extended dorsally.

(Image: modified from Figure 2 Chizhikov VV, Millen KJ., 2005)

Rostro-Caudal

What about the third pattern axis? Brain rostro-caudal axis is generated by differential expression of Hox genes. Hox genes are transcriptional activators. Interestingly, they corresponding to genetic order on chromosome. (Wilkinson et al., Nature, 341, p405, 1989).

SC Organization

Hox Gene Expression-SC

Hox related family of proteins (LIM) contain slightly different DNA-binding domain.

LIM genes originally isolated from C. Elegans ( a worm).

LIM genes differentially expressed along rostro-caudal axis. (Tsuchida, Cell 79, p957, 1994).

LIM Gene Expression

Differential expression means a different member of this protein family is expressed at different segmental levels.

Just as Hox for the brain.

Chicken LIM genes - Islet-1, Islet-2, Lim-1, Lim-3 (Lumsden, Current Biology 5, p491, 1995).

Motoneuron Populations- LIM Expression

Acronyms

MMC- Medial Motor Column (trunk)

MMCm (medial) axial near vertebra

MMCl (lateral) ventral body wall

LMC Lateral Motor Column (limbs) LMCl (dorsal)

CT- Column of Terni (visceral)