Patterning of the Brain

Transcription

1 Patterning of the Brain IoPPN 27 Oct 2015

2 Hundreds of billions of cells, hundreds of cell types

3 Egg = single cell, some 20,000 genes

4 Egg = single cell, some 20,000 genes How is this enormous complexity achieved?

5 A knowledge of the molecular mechanisms that regulate brain development may help us to understand the genetic basis of neurological diseases

6 Underlying principles of brain patterning gradients (morphogens)

7 Underlying principles of brain patterning gradients (morphogens) local signalling centres ( organisers )

8 Underlying principles of brain patterning gradients (morphogens) local signalling centres ( organisers ) segmentation, boundaries

9 The brain/cns is derived from the neural plate days

10 The brain/cns is derived from the neural plate days days

11 Neurulation (modified from Wallingford et al., 2013)

12 Neurulation (modified from Wallingford et al., 2013)

13 Amphibian gastrulation blastula early gastrula mid-gastrula late gastrula An ectoderm dorsal mesoderm D V A P D A Veg mesoderm endoderm V

14 Spemann s organiser induces a fully patterned CNS (Hilde Mangold & Hans Spemann, 1924)

15 The organiser changes its inductive capacity during gastrulation early late (Hans Spemann)

16 Morphogen models in anteroposterior & mediolateral patterning P A (Pieter Nieuwkoop and others)

17 The French Flag Model for morphogen action (Lewis Wolpert) concentration t 2 t 1 0 distance

18 The French Flag Model for morphogen action (Lewis Wolpert) concentration specifies multiple cell fates (>2) acts over a distance (multiple cells) acts directly on the receiving cells t 2 t 1 0 distance

19 Wnt signalling is necessary and sufficient for AP patterning

20 Wnt signalling posteriorises chick neural tissue dose-dependently A Sox2 Otx2 Pax6 En1 Gbx2 Krox20 P Wnt3A (Nordstrom et al., 2002)

21 Wnt is a posteriorising morphogen Wnt P A (Pieter Nieuwkoop and others)

22 Spemann s organiser expresses Wnt inhibitors Crescent Frzb1 sfrp2 Dkk1 (Pera & De Robertis, 2000; Leyns et al., 1997; Hiratani et al., 2003; Glinka et al., 1998)

23 Overexpression of Wnt inhibitors enlarged anterior structures Dkk1 mrna injection

24 Anterior dorsal mesoderm expresses Wnt inhibitors Crescent Frzb1 sfrp2 Dkk1 D A P V (Pera & De Robertis, 2000; Leyns et al., 1997; Hiratani et al., 2003; Glinka et al., 1998)

25 Wnt inhibition is necessary for head formation wild type Dkk1 -/- (Mukhopadhyay et al., 2001)

26 Opposing gradients in anteroposterior patterning [Wnt] [anti-wnt] spinal cord hindbrain midbrain forebrain

27 Underlying principles of brain patterning gradients (morphogens) local signalling centres ( organisers ) segmentation, boundaries

28 From neural plate to neural tube

29 Dorsoventral polarity of the spinal cord (Cajal, 1909)

30 Spinal cord polarity is functionally relevant

31 The notochord is an organiser of the ventral spinal cord

32 The notochord and floor plate secrete Sonic hedgehog (Shh)

33 Shh is a ventralising morphogen

34 Shh gradient class I & II transcription factors

35 Other organisers of spinal cord development

36 Increasing morphological complexity

37 Midbrain inversion experiments FB MB HB Mes Mes2 Cb2 Mes1 Di Tel Cb Cb1 HB

38 The midbrain-hindbrain boundary functions as an organiser (Liu & Joyner, 2001)

39 Expression of Fibroblast growth factor 8 (Fgf8) (E. Laufer)

40 FGF8 mimics the organiser activity of the MHB (Liu & Joyner, 2001)

41 How is the MHB positioned?

42 How is the MHB positioned?

43 Wnt signalling posteriorises chick neural tissue dose-dependently A Sox2 Otx2 Pax6 En1 Gbx2 Krox20 P Wnt3A (Nordstrom et al., 2002)

44 The posteriorising Wnt gradient positions the MHB Wnt gastrula Otx2 Gbx2 neurula FGF8 tectum, cerebellum

45 Progressive subdivision of the neural plate/tube Wnt (Kobayahsi et al., 2002)

46 Orthogonal gradients pattern the neural tube in a quasi-cartesian coordinate system

47 The hindbrain is organised into rhombomeres

48 The hindbrain is organised into rhombomeres

49 Periodic organisation of hindbrain neurons

50 Rhombomeres are cell lineage-restricted compartments

51 Cells from even- and odd-numbered rhombomeres have different adhesive properties (Wizenmann & Lumsden, 1997)

52 Segmental gene expression in the hindbrain

53 Underlying principles of brain patterning gradients (morphogens) local signalling centres ( organisers ) segmentation, boundaries