Patterning the central nervous system 1. master genes 2. induction Neurogenesis, Fate determination during proliferation Fate determination during differentiation Gain of function and loss of function Markers

The early vertebrate brain vesicles and neuromeres

Patterning forebrain Division of telencephalon and diencephalon: BF-1 -/- : deletion of ventral telecephalon and severe reduction of the cortex Lateral neural tube pituitary and mammillary region of hypothalamus Emx1 & Emx2 in pallium Dlx1 & Dlx2 in striatum

1.Otx2 2.Rostral pole of neural plate, row-1, ANR (FGF8 to BF-1), as secondary signaling center, set up by prechordal endoderm

Patterning dorsal telencephalic regions (pallium, future cortex) Genes: Pax6, Tbr1, Emx1<Emx2<Otx1<Otx2 Patterning ventral telencephalic region (LGE, MGE, future striatum and globus pallidus), Dlx, Nkx2.1

Emx1 KO: corpus callosum Emx2 KO: hippocampal dentate gyrus and the CR cells (reeler) Gli3 KO: Disruption of dorsal telecephalic-diencephalic boundary + cortical lamination defects. Further specification of dorsal telencephalon: incoming thalamic afferents Ventral telencephalon Dorsalateral: LGE to striatum Ventromedial: MGE to globus pallidus Nkx2.1 KO, more striatum Pax6 to R-cadherin, LewisX antigen, KO lose corticostriatal boundary Transplantation: community effect (tissue vs. single cells)

Small GABAergic inhibitory interneurons

Diencephalic regionalization Parencephalon: to ventral (anterior) and dorsal (posterior) thalamus, zli (zona limitans intrathalamica) VT ( Dlx1 and Dlx2), DT (Gbx2 and Wnt3) Zli (SHH, mamillothalamic tract) Synencephalon: to anterior, posterior (pretectum) Prosomere: cell lineage restriction, virus?

Zli: transition from epichordal to prechordal regions, SHH, Dlx in ventral thalamus, Gbx2 and Wnt3 in dorsal thalamus. Pax6 in pretetum, vs, En and Pax2 in mesencephalon.

Midbrain Dorsal: tectum, torus semicircularis, (superior and inferior colliculi) Ventral: substantia nigra, ventral tegmental area, motor neurons of oculomotor nerve. Tectum: AP polarity. Epherin (controlled by En)

Patterning of midbrain by isthmus Position of isthmus is decided by Otx2 and Gbx2, (Otx2-/+, Otx1-/-)

Midbrain inversion, En expression Isthmus transplantation Wnt1: maintenance of En FGF8: induction Pax2, 5, 8 for isthmus formation

FGF8 is not enough to induce cerebellum in rostral hindbrain. DV axis is dependent on SHH

Hindbrain

Segmentation and neuronal pattern, rhombomere, boundary, gene expression, pairwise organization

Repetitive reticular neurons Two-segment repeat

Compartment Young neurons vs. ventricular zone

Partition by adhesion EphA4, EphB2, EphB3 in r3, r5 (by Krox20, by Kreisler (r5, r6)) EphrinB in r2, r4, r6

Retinoids on Hox Birth defects in hindbrain Hox expression change RARE Raldh2, in presomitic mesoderm, source Cyp26, inactivates RA in midbrain and forebrain, sink. FGF8 as an anterior inhibitor of Hox and induces cerebellum in r1.

Spinal cord and somites Relay model Gradient model

Pax genes encode DV value?

Target genes of SHH: HNF3 , Nkx2.1, Nkx2.2, Isl1, Pax3, Pax6, Msx1 Sequential induction, RA specification

LMC M : Isl1, Isl2; LMC L : Isl2, Lim1; MMC L : Isl1, Isl2; MMC M : Isl1, Isl2, Lim3, Gsh4 Preganglionic MC: Isl1

Dorsal spinal cord: Slug (neural crest), Lmx1 (roof plate), LH2 (dorsal interneurons)

Role of SHH in ventral forebrain High: MGE Low: LGE SHH as a permissive ventral inducer.

Coordination of AP and DV patterning mechanisms AP identity is formed earlier than DV identity