Neural development its all connected

How do you build a complex nervous system?

How do you build a complex nervous system? 1. Learn how tissue is instructed to become nervous system. Neural induction 2. Learn how the nervous system is patterned to generate distinct neuronal cell types. Neural patterning 3. Learn how neurons send axons and dendrites to proper locations to form synapses with correct neurons. Neural circuits

Developmental biology is understanding how organisms develop (form)

Why should we care about development biology? 1. We can understand the cause of many birth defects. 2. Developmental biology combines cell biology, genetics, biochemistry, evolution, and molecular biology. 3. Stem cells are important and are going to be more important. Developmental biology can teach us how to use them.

Model systems

Developmental stages of Xenopus laevis

Spemann-Mangold organizer and neural induction http://users.rcn.com/jkimball.ma.ultranet/biologypages/s/spemann3.gif

Spemann-Mangold organizer and neural induction http://users.rcn.com/jkimball.ma.ultranet/biologypages/s/spemann3.gif http://www.hhmi.ucla.edu/derobertis/edr_ms/chd_page/ http://images.sciencedaily.com/2005/03/050309130549.jpg

Neural induction: telling tissue to become neuronal http://www.mun.ca/biology/desmid/brian/biol3530/devo_05/ch05f04.jpg

mrna in situ hybridization allows you to visualize where a gene is expressed expressed = mrna is being transcribed

Neural induction can be observed by sox2 expression in the neural plate sox 2 Gee et al., (2011) PLoS One

Xenopus (frog) Drosophila (fruit fly) D D V V

Nerve cord forms on the ventral side of Drosophila embryo D V But similar molecular program is regulating where the nervous system will form Image adapted from Dolan et al. BMC Genomics 2007 8:320 doi:10.1186/1471-2164-8-320

Basic anatomy and regionalization of nervous system underlies distinct functions Breathing - Head and neck Heart rate - Shoulder Wrist and elbow Hand and Finger Sympathetic tone (temperature regulation), Trunk muscles http://healthfavo.com/brain-and-spinal-cord-diagram.html Hips/Pelvic region Knees Knees and Foot Bowl / Bladder

Kelly et al., (1995) Development Wnt8 expression suggests it may regulate A-P patterning Wnt8 Wnt8 D

Over-activating Wnt8 posteriorizes Xenopus embryos Hindbrain Front on view D D Anterior neural plate Kiecker and Niehrs (2001) Development

Wnt Antagonists anteriorize the neural plate DKK FZ8 FRZB1 WNT Kiecker and Niehrs (2001) Development

Summary of anterior-posterior neural patterning DKK http://www.uni-heidelberg.de/md/izn/researchgroups/niehrs/niehrs_fig2.jpg

Distinct domains with sharp borders form by local refinement of gradient information.

At this point we have 1. induced a plate of cells to become neuronal 2. told all the cells within that plate their relative position along the anterior-posterior axis

The neural plate folds and closes to form the neural tube. Tanabe and Jessel Science, Vol 274, Issue 5290, 1115-1123, 15 November 1996 http://www.google.com/search?q=neural+image&client=safari&rls=en&source=lnms&tbm=isch&sa=x&ei=slslutzkbu2w4aoh-oh4dq&ved=0cacq_auoaq&biw=1317&bih=660#q=neurula+image&rls=en&tbm=isch&facrc=_&imgdii=_&imgrc=kvoqsytj_vrvhm%3a%3bjwyq_yroz7tr4m%3bhttp%253a%252f%252fwww.muhlenberg.edu%252fimages %252Fmain%252Facademics%252Fbiology%252Fcourses%252Fbio240%252Fmid_neurula.jpg%3Bhttp%253A%252F%252Fmuhlenberg.edu%252Fdepts%252Fbiology%252Fcourses%252Fbio240%252Famphibian.html%3B700%3B550

The neural plate folds and closes to form the neural tube. Tanabe and Jessel Science, Vol 274, Issue 5290, 1115-1123, 15 November 1996

Dorsal-Ventral patterning in the neural tube generates distinct domains that give rise to specific neuronal types http://www.nimr.mrc.ac.uk/research/james-briscoe/elucidation-of-thetranscriptional-network

Dorsal-Ventral patterning in the neural tube generates distinct domains that give rise to specific neuronal types Wilson and Maden, (2005) Developmental Biology (282) http://www.nimr.mrc.ac.uk/research/james-briscoe/elucidation-of-thetranscriptional-network

The basics of axon guidance L. Erskine, E. Herrera / Developmental Biology 308 (2007) 1 14

The basics of axon guidance Growth Cone L. Erskine, E. Herrera / Developmental Biology 308 (2007) 1 14

http://cellix.imba.oeaw.ac.at/motility/lamellipodia

The basics of axon guidance - The growing region also needs to adhere to a substrate to stabilize the outgrowth and allow progression in one direction.

Axon pathfinding in the Superior Colliculus L. Erskine, E. Herrera / Developmental Biology 308 (2007) 1 14

Summary: 1. Neural induction is caused by inhibition of BMP by CHD and NOG, and by FGF promoting sox2 expression. 2. Anterior neural fates arise during induction and the action of a WNT8 gradient posteriorizes the neural tissue. 3. Opposing gradients of SHH and BMP pattern the dorsal-ventral axis of the spinal cord. 4. Regulating attraction and repulsion guides axons to their target regions 5. Local interactions allow for synapse formation and plasticity over time

Two questions in my lab: What is the relationship between neural development and regeneration? How do nervous systems evolve? (a developmental perspective) Nematostella vectensis:

Nematostella has key features of a good model system 1. Large broods externally fertilized 2. Extensive regenerative capacity 3. Sequenced annotated genome 4. Amenable to genetic manipulation 5. Transparent 6. Transgenic lines 7. Genome is highly conserved to vertebrate genome

Neurogenesis initiates during embryogenesis Nematostella possesses a nerve net embryonic* larval* juvenile* NvashA NvashA NvElav::mCherry

Neurogenesis initiates during embryogenesis embryonic* larval* juvenile* NvashA NvashA

How are the metazoan nervous systems related? non-bilaterian metazoans Possesses nervous system

How are the metazoan nervous systems related? non-bilaterian metazoans? Possible nervous system origin Possesses nervous system

How are the metazoan nervous systems related? non-bilaterian metazoans??? Possible nervous system origin Possesses nervous system

How are the metazoan nervous systems related? non-bilaterian metazoans????? Possible nervous system origin Possesses nervous system

How are the metazoan nervous systems related? non-bilaterian metazoans????? Possible nervous system origin Possesses nervous system How does a functional nervous system develop?

Neurogenesis is continuous during Nematostella development embryonic* larval* juvenile* NvashA::mCherry Nvserum amyloida-like::mcherry NvLWamide-like::mCherry Nvelav Cnidocytes in situ 242483 NvLWamide-like

We disrupt gene function using microinjection to find the neural genes Inject mrna:venus Isolate RNA From Both 24 Hrs @ 25*C

Summary of some of the molecular findings in anemone neurogenesis NvashA Neurons NvsoxB2 Neurons Neurons Nvnotch Nvsix3/6 Nvfgfra WNT

How are the metazoan nervous systems related? non-bilaterian metazoans??? Common origin for nervous system Possible nervous system origin Nervous system of bilaterians and cnidarians likely share a common origin

Two interests in my lab: What is the relationship between neural development and regeneration? How do nervous systems evolve? (a developmental perspective)

What is the relationship between development and regeneration? - Differences exist between the two processes - Critical for developing regenerative therapies - Studied by Thomas Hunt Morgan

What is the relationship between development and regeneration? - Differences exist between the two processes - Critical for developing regenerative therapies - Studied by Thomas Hunt Morgan "You are being very foolish... we will never understand the phenomena of development and regeneration" - Thomas Hunt Morgan in a letter to N.J. Berrill

Nematostella as a model for development and regeneration

We can now identify and characterize subsets of the nerve net during development and regeneration NvLWamide::mCherry

Future directions to investigate neural regeneration: 1. How do axons grow into non-regenerating tissue? 2. How do axons grow into regenerating tissue?

COURSES IN DEVELOPMENTAL BIOLOGY DEVELOPMENT AND DISEASE (BIOS 376) (spring 2016) EVOLUTION AND DEVELOPMENT (BIOS 3##) (spring 2015, Fall 2015, Fall 2016) Questions?

Transgenic animals allow us to visualize the nervous system Transgenes and transgenics Enhancer elements coding sequence green fluorescent protein