Milestones in Developmental Neurobiology

The field of Developmental Neurobiology, within the umbrella of Developmental Biology, has grown in parallel with the parent discipline. The following milestones have been sifted only to highlight the significant achievements in Developmental Neurobiology*.

1907. R. Harrison shows that axons grow out from neuronal cell bodies, founding the field of developmental neurobiology, and invents tissue culture in the course of these experiments.

1917. S. Detwiler studies the origin of the neural crest and the mechanisms of spinal nerve development.

1924. H. Spemann develops microsurgical techniques for embryos and with H. Mangold, discovers the organizer and the phenomenon of neural induction.

1933. C. H. Waddington discovers that Hensen's node is equivalent to Spemann's organizer, and shows that the role of the organizer in neural induction is conserved across species.

1934. Using limb bud ablations, V. Hamburger shows that survival of motor neurons within the spinal cord depends on interactions with the periphery. This insight leads to the discovery of NGF and to the 1986 Nobel Prize to S. Cohen and R. Levi-Montalcini.

1965. R. Watterson shows that cells undergo interkinetic nuclear migration within the wall of the neural tube. It was later shown that this phenomenon occurs throughout development as neurons and glia are born, and that cells migrate within the wall of the neural tube to occupy new locations (P. Rakic and co-workers).

1966. G. Rosenquist generate more accurate fate of blastula, gatrula and neurula by using triated labelled thymidine in unlabelled embryos. This technique was used by J. Weston and D. Noden to map the fate of neural crest cells.

1971. T. Schroeder proposes that neurulation involves the constriction of apical bands of microfilaments within the neural plate.

1976. A.G. Jacobson and R. Gordon show that shaping of the neural plate and closure of the neural groove require convergent extension movements.

1980. G. Schoenwolf and co-workers study the cellular basis of morphogenetic movements of neurulation, showing that bending of neural plate requires intrinsic and extrinsic forces.

1985. R. Keller and co-workers use the so-called "Keller sandwiches" to study the morphogenetic movements of gastrulation. T. Doniach, J. Gerhart and C. Phillips used the same model to study planar signalling during neural induction.

1989. T. Jessell and co-workers' cellular and molecular studies of dorsoventral patterning (especially of the spinal cord), show the importance of the notochord and floor plate in dorsoventral patterning, and the role of sonic hedgehog in floor plate and motor neuron induction.

1990. Knockout mice are used to study dorsoventral patterning of the neural tube by P. Beachy and co-workers; T. Jessell and co-workers; M. Tessier-lavigne and co-workers.

1990. Knockout mice are used to study rostrocaudal patterning in hindbrain by M. Capechhi and co-workers; D. Wilkinson and co-workers, in midbrain by A. Joyner and co-workers; A. McMahon and co-workers; G. Martin and co-workers, and in forebrain by J. Rubenstein and co-workers.

1990- 2001. G. Schoefnwolf and co-workers and C. Stern and co-workers determine cell-fate mapping using flourescent dye injections.

Early 1990-2001. Molecular markers are used to identify the subpopulations of cells, reducing reliance on morphology and increasing specificity and resolution of the experimental analysis. These markers are used simultaneously in chick, mouse and zebrafish embryos.

1990-2001. Rostrocaudal patterning is established using cellular and molecular studies; by R. Krumalauf and co-workers, and A. Lumsden and co-workers in hindbrain; by R. Alvarado-Mallart, L. Bally Cuif and M. Wassef; D. Darnell and G. Schoenwolf in midbrain, and by L. Puelles and J. Rubenstein in forebrain.

Late 1990s-2001. Mutant fish are used to study neural induction, rostrocaudal and dorsoventral patterning, and axonal guidance by W. Driever, J. Eisen, M. Halpern, P. Ingham, C. Kimmel, C. Nusslein-Volhard.

1992. J. Eisen, D. Raible, J. Weston and co-workers map neural crest migration through injection of the single cells and time lapse videomicroscopy, and subsequently in 1996 screen embryos for mutations that affect neural crest migration.

1993. R. Harland and co-workers identify noggin, the first candidate neural inducer, by taking advantage of animal cap assays.

1993. Dr. Turner and H. Weintraub show that basic Helix Loop Helix (bHLH) achaete scute-like gene (NeuroD) induce ectopic neurons when overexpressed, as they do in drosophila.

1994. A. Hemmati-Brivanlou and D. Melton identify follistatin, a candidate neural inducer known to inhibit activin. By inactivating TGF-β signalling, they further show that default state of the extoderm is neural, not epidermal as previously believed.

1994-1996. E. DE Robertis and Y. Sasai identify chordin, a candidate neural inducer that binds to BMPs to block their signalling.

1994. R. Beddington shows that the node induces a secondary body axis that lacks a head when transplanted to an ectopic site in the gastrula.

1995. Molecular and cellular organization of the organizer by G. Schoenwolf and co-workers and C. Stern and co-workers.

1995. A. Chitnis and co-workers show that lateral inhibition acts in the vertebrate neural plate through Notch-Delta signalling in a manner similar to that found in the invertebrate ventral nerve cord.

1998. R. Beddington, E. Robertson and their co-workers identify the anterior visceral endoderm as a signalling centre equivalent to the head organizer of amphibians.

1998. C. Nusslein-Volhard and co-workers use a large-scale mutagenesis screen to identify genes that have unique and essential functions during development.

A cursory look at these achievements tells us that earlier discoveries within developmental neuroscience were widely spaced. However, the decade of 1990-2001 saw many more of these discoveries. The discipline's progress paralleled with significant developments in technology. As the tools to study the developmental processes got sophisticated, we saw more and more new findings in almost every existing discipline of biology including developmental neuroscience. Dr. Fiona Watt, the current chairperson of International Society for Stem Cell Research asserts that we are sitting on an information gold mine. We need the tools to analyze that data in a comprehensive fashion. Systems Biology has already revolutionized many fields of biological research. The reductionist approach that has been our main tool to study biological phenomenon is being reinforced by this emerging science. I can foresee the day, that I think isn't far now, when we will have a complete picture of processes that once considered to be isolated which, infact, are very intricate, interwoven and interdependent.

* Nat. Rev. Neurosci. 2, 763-771 (2001).
* Nat. Rev. Neurosci. 5, S526-527 (2004).

Adult Neurogenesis

The book is finally out, and I am anxious to get my hands on it. Dr. Fred Gage has summarized the concepts of neurogenesis with a comparative analysis of the phenomenon in various species. The thirty chapters that the book contains are contributed by the leading scientists in this discipline such as Dr. Pasko R. Rakic, Dr. Arturo Alvarez-Buylla, Dr. Alfredo Quinones-Hinojosa, Dr. J. W. Schneider including Dr. Gage himself, to mention a few. The monograph is available at the Cold Spring Harbor Laboratory Press.

Another Milestone in Stem Cell Research

This year only 33% of the submitted proposals for generating new cell lines got funded by the California State. California Institute of Regenerative Medicine initially rejected the proposal of Dr. Fred Gage of Salk Institute, an affiliate of the University of California, San Diego. Only upon receiving a letter from the great scientist about why that particular proposal was important, Dr. Gage won the funding. I haven't seen his manuscript, and I haven't even read the reviewers comments about why the proposal was rejected in the first place but that does raise some curiosity and suspicion about the review process at CIRM.

On another note, few months back I had the opportunity to meet with a Harvard professor who was trained by Dr. Rudolf Jaenisch at MIT. We discussed his work for a while before discussing different projects. Dr. Jaenisch had discovered a glitch in the apparent flawless discovery of the Dr. James A. Thomson and Dr. Shiniya Yamanaka that the induced Pleuripotent Stem Cells (iPS) obtained from mouse fibroblasts didn't actually yield an embryo. In order for them to become true embryonal stem cells certain factors must be activated in exact chronological sequence. Earlier, Dr. Jaenisch had done that successfully and he was able to generate mice using that technique. The July 1 issue of Nature Biotechnology now reports another marvelous achievement by the genius of Dr. Janisch. This time Doxycyclin has done the trick, obviating the need for further genetic manipulation of iPS cells. All scientists need to do now is to add those four factors to obtain iPS cells and with the addition of the drug, Doxycyclin they can obtain cells that can give rise to embryonal stem cells or become the source of tissue specific embryonic stem cells from any tissue within body. Isn't that amazing?