Rostral-Caudal Patterning

Noggin - role in neurulation

(mesodermal origin - from organizer - when stained, concentrated in skeletal structures) 1. Inhibits BMP = formation of neural tissue 2. Transforms early neural tube tissue into ROSTRAL brain structures

Retinoic acid

- Acts as transformer to create posterior neural tube - Does NOT INDUCE neural tissue but TRANSFORMS anterior neural tube tissue into posterior neural tube tissue phenotype - RA comes from segmented mesodermal tissue such as the notochord - Also alters Hox gene expression - Expressed in a gradient (HIGHER in posterior neural tube

Spina bifida

- Can be mild or severe - Severe form can be characterized by myelomeningocele, where unfused spinal vertebrate allow spinal cord and meninges to protrude - Nerves often become damaged; loss of function at or below the level of spina bifida can occur

Closure of the neural tube

- Does not occur all at once - zipper-like - Begins approximately at level of fourth somite (future cervical cord region) around E20 in humans - Lateral edges of the neural plate touch the midline and join. This continues both cranially and caudally. - Openings at either end are termed cranial/caudal neuropores. - In human embryos, the cranial neuropore closes at approximately E25 and the caudal neuropore at appropximately E27.

Anencephaly

- Lack of telencephalon (forebrain or cerebrum, the thinking part of the brain in humans) - Incidence ~ 3 in 10 000 pregnancies - Rostral end of neural tube fails to close. - Almost always fatal, most fetuses spontaneously abort. Cart1 gene has been implicated - Cart1 homozygous mutant mice lack telencephalon - Folic acid (vitamin B9) appears to reduce incidence of anencephaly in the mutant mice

Role of Hox in Drosophila

- Mutagenic studies in Drosophila revealed that some mutations can give rise to homeotic transformations (conversion of one segment into another)

Accutane

- Prescribed for acne; contains ISRETINOIN, a vitamin A analog - Withdrawn from the market in 2009 but generic versions are still available - Potent teratogen at very low doses (critical window = first 3-5 weeks of pregnancy) Birth defects can be SEVERE. Microcephaly, neural tube defects, craniofacial malformations. 50% of affected children have IQs below 85.

Role of folate to prevent neural tube defects

- Prophylactic folate (vitamin B9) and B12 supplements can REDUCE incidence of anencephaly and spina bifida - Folate is important for DNA methylation during DNA synthesis, associated with rapid neural cell proliferation and needed for post-translational methylation of cytoskeleton during closure of neural tube - Folate supplements can reduce the predisposition for high demands of folate early in development - Folate are added to flour used for all baked goods in Canada. Other sources: avocadoes, asparagus, leafy greens, vinegar However, as many as 30% of neural tube defects are NOT linked back to lack of dietary folate

Same gene/protein can have different effects depending on

1. Cell location 2. Timing of expression 3. Amount of expression 4. Expression of COMPLEMENTARY molecules***

Transforming signals

1. Retinoic acid (vitamin A metabolite) 2. FGF 3. Wnt

Failures of neural tube closure

1. Spina bifida 2. Anencephaly

Human Hox gene disorders

1. Syndactyly - Hox + several other genes are involved in defining digit patterns. Fusion of 2nd/3rd digits 2. Synpolydactyly - Mutations in Hox13 on Chromosome 2 --> 3rd and 4th digit linked by webbing, + an extra digit

Proencephalon -->

1. Telencephalon 2. Diencephalon

Niewkoop's Model of Neural Induction

Activation-Transformation Model Signals from the organizer induce anterior neural tissue FIRST ('activation') that is subsequently posteriorized to elaborate the anterior-posterior axis of brain/spinal cord. 1. BMP inhibitors generate rostral (anterior) tissue FIRST / Wnt antagonists secreted by Spemann's organizer induce anterior neural tissue. 2. Wnt antagonists shape Wnt activity gradient

Differentiation of brain vesicles

Anterior neural tube bulges into 3 primary vesicles, then differentiates into 5 secondary vesicles. 1) Proencephalon 2) Mesencephalon 3) Rhombencephalon (+ Caudal neural tube)

Ectoderm during neurulation

Divided into three types of cells: 1) Neural Tube 2) Neural Crest 3) Epidermis (skin)

Neural Crest

Forms peripheral nervous system, pigment cells, and other cells.

Neural Tube

Forms the brain/spinal cord. FGF expression is higher in POSTERIOR neural tube, resulting in spinal cord as opposed to brain tissue.

Action of BMP inhibitors

Generate rostral (anterior) neural tissue first Double KO mice (KO chordin/noggin) lack rostral brain structures, but caudal brain structures (brainstem/spinal cord) are still relatively normal.

FGF expression

Higher in posterior neural tube. FGF + Noggin (BMP inhibitor) contribute to a more complete rostral/caudal patterning

Antennapedia

Hox mutation in Drosophila GOF - legs grow in place of antennae LOF - antennae grow in place of second pair of legs

Ultrabithorax

LOF Hox mutation in Drosophila appendage on T3 segment is normally a haltere (a small balancing organ) - Normally Ubx prevents T3 from taking on 2nd segment phenotype - Mutant deficient in Ubx expression grows a second wing instead of a haltere (LOF)

Mesencephalon-->

Mesencephalon (midbrain)

Rhombencephalon-->

Metencephalon (pons/cerebellum) Myelencephalon (medulla)

AP neuraxis

Patterned by interplay between posteriorizing Wnt and anteriorizing Wnt antagonists secreted by Spemann's organizer (anteriorizing Wnt antagonists are HIGHER in rostral segments)

Role of Hox genes

RA and Wnt regulate differential expression of Hox genes along the rostral-caudal axis. Hox genes and their products (Hox proteins) determine the type of subsequent structures that arise from the initial basic embryonic segments - A class of regulatory genes that code nuclear proteins (homeoproteins) that mostly act as transcription factors - Hox genes bind to specific nucleotide sequences on DNA called enhancers where they either activate or repress genes - The same Hox protein can act as an activator at one gene and a represser at another - Hox genes can regulate cascades of genes simultaneously SUPER PHYLOGENETICALLY CONSERVED = very important, and a chicken Hox gene can sub for a Drosophila hox gene and lose no function

Posterior neural development

RA, FGF, Wnt contribute to posteriorizing neural tube.

Wnt antagonists

Secreted by Spemann's organizer, induce anterior neural tissue. Establish a Wnt activity gradient in the neural ectoderm where there are MORE Wnt ANTAGONISTS in ROSTRAL segments. 1. Dickkopf: induces amphibian head formation. NECESSARY but not sufficient alone 2. Frzb1: induces head enlargement 3. Cerberus: head formation

Rhombomeres

Vertebrate hindbrain is segmented early in neural development. - 8 rhombomeres, subtypes of motor neurons - Overlapping Hox gene expression confers rhombomere identity Repeated, segment-like transient swelling in the hindbrain. - Defined by banded expression of Hox and other related genes. - Later mature into pons, cerebellum, and the medulla

Wnt/B-catenin pathway

Wnt = role in posterior neural tube specification - Wnt --> removes Axin from Axin-GSK3-APC complex --> stops degradation of B-catenin --> less effect on Hox genes - B-catenin gradient along neural tube The Wnt/B-catenin pathway subsequently influences SEGMENTAL SPINAL CORD specific HOX gene expression. (High B-catenin in spinal cord, decreasing up to near absence of staining in forebrain) Higher B-catenin staining means more Wnt activity. So Wnt activity is higher in posterior (caudal) end.

Head induction

Wnt antagonism + BMP antagonism = head induction

Anterior neural development

Wnt inhibition + BMP inhibition