BRAIN DEVELOPMENT I: ESTABLISHMENT OF BASIC ARCHITECTURE. Thomas Marino, Ph.D.

Transcription

1 BRAIN DEVELOPMENT I: ESTABLISHMENT OF BASIC ARCHITECTURE Thomas Marino, Ph.D.

2 Development of the Brain I. Competencies: Upon completion of this section of the course, the student must be able to: 1. Understand the development of the neural tube into the spinal cord and brain regions. 2. Remember which part of the developing brain developed into the specific brainstem regions. 3. Recall the factors involved in the dorsoventral organization of the brain and spinal cord.

3 Neural Development In the developing nervous system there must be: 1. The formation of different regions of the brain. 2. The ability of a neuron to differentiate. 3. The ability of axons to go to an appropriate location. 4. The ability to set up synaptic circuits. 5. The consolidation and maturation of neural connections.

4 Introduction The development of the brain starts with the basic neural tube seen in the spinal cord. The neural tube changes in the different regions. Early development is largely dependent upon the molecular and genetic machinery that directs these events.

5 Trilaminar Embryo Ectoderm mesoderm Notochord Endoderm

6 Ectoderm Oral Plate Prechordal Plate Notochord Neural Plate

7 Early Development Day 19 Day 21 Day 22

8 Ectoderm Somites Pericardial Bulge Neural Tube

9 Ectoderm Cranial Neuropore Pericardial Bulge Somites Caudal Neuropore

10 UNSW Embryology

11 Development of the Neural Tube

12 Development of the Neural Tube

13 Lateral Body Folding Surface ectoderm Amniotic Cavity Paraxial mesoderm Neural Tube Intemediate mesoderm Body Cavity Chorionic Cavity

14 UNSW Embryology

15 Dermomyotome WNT PAX3 Scleretome (PAX1) SHH

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17 The Development of Different Brain Regions. The basic organization of the CNS is into: alar plate sensory cells basal plate motor cells The alar and basal plate cells are organized on either side of the sulcus limitans.

18 The Development of Different Brain Regions. Alar Plate: represents the sensory region of the gray matter. Basal Plate: represents the motor region of the gray matter Sulcus Limitans

19 Dorsal-Ventral Patterning So what regulates the organization of the CNS into dorsal and ventral regions?

20 The Development of Different In the forebrain SHH induces NKX2 Which induces the hypothalamus. Brain Regions.

21 The Development of Different Brain Regions. But SHH actually has the effect of ventralizing the entire CNS.

22 The Development of Different Brain Regions. Notochord secretes SHH (red) Ventral floor plate then secretes SHH as well. If two notochords then two floor plates. If you remove notochord then no ventral part of the neural tube.

23 The Development of Different Brain Regions. SHH induces the differentiation of the floor plate Bmps are expressed in the epidermis Eventually are expressed in the dorsal neural tube. Neural crest cells are located at the epidermis/neural tube junction (blue) Motor neurons (yellow) expressing Isl1 appear in the ventral neural tube.

24 The Development of Different Gradient of SHH regulate the cell types in the basal plate. V0 V3 interneurons MN motor neurons Brain Regions. N

25 The Development of Different Brain Regions. SHH induces NKX2.2, Nkx6.1 SHH represses Pax6, Pax7, DBX1, Dbx2 Fuzzy gradients set up Then interaction in the expression of the genes sharpens the borders and allows for determination of different cell types.

26 Major take-home message Different genes are expressed in different regions of the spinal cord and help determine dorsal-ventral polarity. HNK1 Pax3 msx Slug Pax7 ISL1 HNF3β Nkx2.2

27 Development of the Brain

28 The Development of Different Brain Regions. Prosencephalon Mesencephalon Rhombencephalon

29 The Development of Different Brain Regions. Prosencephalon Mesencephalon Telencephalon Diencephalon Mesencephalon Rhombencephalon Metencephalon Mylencephalon

30 The Development of Different Brain Regions. What factors help control the development of different regions of the CNS?

31 The Development of Different Brain Regions. The hindbrain has 8 rhombomeres. Variably express HOX genes Their pattern of expression overlaps. Convey positional value along the AP axis Retinoids play a regulatory role

32 The Development of Different Brain Regions. As you reach the midbrain the hox genes are not expressed. The midbrain-hindbrain boundary (MHB) is found. MHB

33 The Development of Different OTX expressed in neural plate Designates midbrain. Brain Regions.

34 The Development of Different Once OTX is expressed then: FGF8 is signaling molecule for: Engrailed (En) is critical for the development of this region. WNT1 and IRX2 important in cerebellum development. Pax2 also plays a role. Brain Regions.

35 The Development of Different In the forebrain Anterior neural ridge secretes FGF8 FGF8 induces Brain Factor s1 (BF1) BF1 regulates the development of the telecephalon. NKX2,1 regulates the development of the hypothalamus. Brain Regions.

36 Major take-home message This early formation of the brain is independent of neuronal activity.

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38 The Development of Different Brain Regions. Telencephalon Cerebral Hemisphere Diencephalon Mesencephalon Diencephalon Midbrain Metencephalon Pons and cerebellum Mylencephalon Medulla

39 Low Medulla Alar Plate Nucleus Gracilis Nucleus Cuneatus Basal Plate Pyramids

40 Transition to higher medulla The pontine flexure pushes out the dorsomedial neural tube. In the cephalic mylencephalon the roof plate then thins out. Pia Ependyma

41 Alar Plate High Medulla 4th Ventricle Roof plate Choroid Plexus Basal Plate

42 The Development of Different Brain Regions. Telencephalon Cerebral Hemisphere Diencephalon Mesencephalon Diencephalon Midbrain Metencephalon Pons and cerebellum Mylencephalon Medulla

43 Clinical significance Holoprosencephaly and fusion of the eyes (synophthalmia) Lateral ventricles fuse into one chamber Eye fields do not separate Other midline facial defects. Olfactory bulbs may be absent. Corpus callosum absent

44 Holoprosencephaly Mutations in SHH Also defective cholesterol biosynthesis Smith-Lemli-Opitz Loss of 7-dehydrocholesterol reductase Can not make cholesterol Cholesterol necessary for SHH to be effective. Also seen in alcohol abuse.