Neural development its all connected

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1 Neural development its all connected

2 How do you build a complex nervous system?

3 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

4 Developmental biology is understanding how organisms develop (form)

5 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.

6 Model systems

7 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

8 Developmental stages of Xenopus laevis

9 Spemann-Mangold organizer and neural induction

10 Spemann-Mangold organizer and neural induction

11 Neural induction: telling tissue to become neuronal

12 Neural induction: telling tissue to become neuronal

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

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

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

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

17 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 :320 doi: /

18 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

19 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 Hips/Pelvic region Knees Knees and Foot Bowl / Bladder

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

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

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

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

24 Summary of anterior-posterior neural patterning DKK

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

26 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

27 The neural plate folds and closes to form the neural tube. Tanabe and Jessel Science, Vol 274, Issue 5290, , 15 November %252Fmain%252Facademics%252Fbiology%252Fcourses%252Fbio240%252Fmid_neurula.jpg%3Bhttp%253A%252F%252Fmuhlenberg.edu%252Fdepts%252Fbiology%252Fcourses%252Fbio240%252Famphibian.html%3B700%3B550

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

29 Dorsal-Ventral patterning in the neural tube generates distinct domains that give rise to specific neuronal types

30 Dorsal-Ventral patterning in the neural tube generates distinct domains that give rise to specific neuronal types Wilson and Maden, (2005) Developmental Biology (282)

31 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

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

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

34

35

36 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.

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

38 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

39 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 a common theme is that gradients pattern neural tissue Any one cell has 3 dimensions of patterning A-P, D-V, and Time

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

41 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

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

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

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

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

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

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

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

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

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

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

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

53 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

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

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

56 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

57 Nematostella as a model for development and regeneration

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

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

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

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

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

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

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