**3. Stages in telencephalic development**

A fundamental feature of the nervous system development is the precise temporal sequence of cell type generation. The first neural cells, **neuroepithelial (NE) cells**, arise from the pluri‐ potent stem cells of the early blastocyst that differentiate from the ectoderm towards the neuroectoderm through a process named **neural induction** [16;17].

Morphologically, NE cells are columnar epithelial cells which form the neural plate and later on the ventricular zone (VZ) of the neural tube. They are considered to be primordial neural stem cells that give rise to various types of neurons, followed by glial cells [18-20]. The ela‐ borated process by which NE cells progress towards telencephalic neurons can be divided into several discrete stages:


The **signaling pathways** controlling the neural cell fate specification during these stages have been the focus of intense research in the recent years [4;19;24-27]. Extrinsic factors, named **morphogens,** induce two or more different cell fates in a concentration-dependent manner by modulating the expression and activity of specific **TF.** The TF can in turn modu‐ late the secretion of morphogens. The combinatorial expression of these TF instructs each unique NP population to generate progenies that are committed to specific neural fates.

## **4. Stage-related morphogens in mouse telencephalic neurogenesis**

The morphogens known to play a role during telencephalon development are: sonic hedgehog (SHH), fibroblast growth factors (FGFs), bone morphogenetic proteins (BMPs), Wingless/INT proteins (WNTs), transforming growth factors (TGFs) and retinoic acid (RA). They are secreted from specific centers, named organizers, during early stages of development [28].

Genetic evidence based on loss- and gain-of-function studies have indicated that the role of these morphogens can be rather complex. Depending on the developmental stage it ranges from establishment of general patterning characteristics to neuronal specification [5;21;23;26;29-33].

#### **4.1. Early A/P patterning**

**Cholinergic** neurons in the telencephalon (both *interneurons* and *projection neurons*) are gen‐ erated in the MGE. First, cholinergic projection neurons are produced by vMGE, followed by the production of cholinergic interneurons from dMGE, at later time points. Cholinergic interneurons populate the striatum; cholinergic projection neurons populate the pallidum

A fundamental feature of the nervous system development is the precise temporal sequence of cell type generation. The first neural cells, **neuroepithelial (NE) cells**, arise from the pluri‐ potent stem cells of the early blastocyst that differentiate from the ectoderm towards the

Morphologically, NE cells are columnar epithelial cells which form the neural plate and later on the ventricular zone (VZ) of the neural tube. They are considered to be primordial neural stem cells that give rise to various types of neurons, followed by glial cells [18-20]. The ela‐ borated process by which NE cells progress towards telencephalic neurons can be divided

**1. Early anterior/posterior (A/P) patterning.** The NE cells in the neural plate acquire an

**2. Dorsal/ventral (D/V) patterning.** Once the neural tube is formed and the telencephalic primordium is established, it is subdivided into discrete territories where the NE cells proliferate and transform into neural progenitor (NP) cells that reside in the adjacent newly-formed subventricular zone (SVZ). In the dorsal telencephalon, the NP cells are radial glia and basal (or intermediate) progenitors [5;21-23]. Different progenitor do‐

**3. Neuronal specification.** Each of the progenitor domains produces specific types of neu‐ rons which further develop different neurotransmitter identities and connectivity patterns.

The **signaling pathways** controlling the neural cell fate specification during these stages have been the focus of intense research in the recent years [4;19;24-27]. Extrinsic factors, named **morphogens,** induce two or more different cell fates in a concentration-dependent manner by modulating the expression and activity of specific **TF.** The TF can in turn modu‐ late the secretion of morphogens. The combinatorial expression of these TF instructs each unique NP population to generate progenies that are committed to specific neural fates.

**4. Stage-related morphogens in mouse telencephalic neurogenesis**

The morphogens known to play a role during telencephalon development are: sonic hedgehog (SHH), fibroblast growth factors (FGFs), bone morphogenetic proteins (BMPs),

A/P identity; the anterior ones give rise to the telencephalic primordium.

mains are formed in the ventral telencephalon: MGE, LGE and CGE.

and the septum and project mainly to neocortex and hippocampus, respectively [15].

**3. Stages in telencephalic development**

220 Trends in Cell Signaling Pathways in Neuronal Fate Decision

into several discrete stages:

neuroectoderm through a process named **neural induction** [16;17].

A/P patterning starts to emerge in parallel with neural induction, prior to and during gas‐ trulation. At embryonic day (E) 8.5, in regions of the embryo protected from the influence of caudalizing factors, such as WNTs, BMPs, and RA, or where their antagonists are secreted, such as Dickkopf1 (DKK1), an inhibitor of the WNT signaling pathway, and Noggin, an in‐ hibitor of the BMP signaling pathway, the NE cells develop an anterior character and form the prospective forebrain (future telencephalon and diencephalon) [28;33-35]. FGFs (e.g. FGF8, FGF15, FGF3) are expressed early on at the anterior tip of the neural plate and then maintained in the anterior limit of the neural tube [32]. Although not a primary inducer of the telencephalic fate, FGF signaling influences the telencephalic gene expression [32;36].

#### **4.2. D/V patterning**

With regard to the location and timing of telencephalic progenitor generation, different ex‐ trinsic factors are involved in their patterning and self-renewal. WNTs and BMPs pattern the telencephalic progenitors dorsally, while SHH patterns them ventrally. BMPs are ex‐ pressed dorso-medially and are required for the formation of the choroid plaque and the cortical hem [31;37;38]. WNTs are secreted from the cortical hem and promote the develop‐ ment of the hippocampus [30]. The expression of SHH is first observed at E8.5 in structures adjacent to the ventral telencephalon, and by E9.5 in the MGE and preoptic regions [29]. SHH promotes the formation of all ventral telencephalic subdivisions [29;39-41]. FGFs are involved in both ventral and dorsal patterning [27;30;32;42;43]. Activin, a TGF-related mole‐ cule, acts ventrally in the CGE patterning [44]. RA contributes to the patterning of the lateral telencephalon and participates in setting-up the D/V boundary [45-49].

#### **4.3. Neuronal specification**

The balance between the signaling inputs that control NP self-renewal and differentiation is critical for the initiation of the terminal differentiation program. FGFs and SHH, in addition to their patterning activities, promote self-renewal and prevent differentiation, while RA promotes neuronal differentiation [1;47]. Notably, it has been shown that the expression of SHH is required during distinct developmental windows for the specification of neuronal identity [29]. FGF signaling may ultimately influence the generation of cell diversity within the ventral telencephalon [30;50]. WNT promotes neuronal differentiation in different late cortical progenitor cell populations [51]. BMPs inhibit neurogenesis but could participate in late neuronal specification and maturation of different subpopulations [52]. Activin is also a potent neurotrophic factor that induces differentiation of telencephalic neural precursors in‐ to calretinin-positive cortical interneurons [44].

The central mechanism that determines NP D/V patterning is the activity of the Gli family of transcriptional regulators–Gli1, Gli2, and Gli3. SHH promotes the formation of a ventral tel‐ encephalic subdivision by inhibiting the dorsalizing effects of Gli3 [27;35;56;68]. Gli3 is high‐ ly expressed dorsally, with lower expression in the LGE and MGE. Gli1 is expressed ventrally, at high levels in the progenitor domain of the dMGE and vLGE, whereas Gli2 is highly expressed in the progenitor domain of the dorsal telencephalon, with a lower expres‐

Telencephalic Neurogenesis Versus Telencephalic Differentiation of Pluripotent Stem Cells

http://dx.doi.org/10.5772/54251

223

**Figure 2.** The domains of the main transcription factors implied in dorsal-ventral patterning in mouse embryonic

The mechanisms of neuronal specification in the dorsal telencephalon have been extensively studied in the context of cerebral cortex development. The dorsal progenitors produce neu‐ rons, in a tightly controlled temporal order from E10.5 to E17.5. Pax6, Ngn1 and Ngn2 in‐ struct **glutamatergic** identity and inhibit astroglial differentiation [69-72]. The differentiation by Ngns involves the sequential activation of the expression of other TF such as NeuroD, Tbr1 and Tbr2 [69]. NeuroD has been implicated in the terminal differentiation of the hippo‐ campus [73]. The differentiation of specific populations of projection neurons is controlled by neuronal subtype-specific genes, which have only begun to be identified. The timing of cortical neurogenesis is encoded within lineages of individual progenitor cells, with differ‐

The earliest born neurons form a layered structure termed the preplate, which is later split into the superficial marginal zone and the deeply located subplate. The cortical plate, which will give rise to six-layered neocortex, begins to develop between these two layers. The later born neurons arriving at the cortical plate migrate past earlier born neurons [5;74]. During development, neurons in different layers are generated in an inside-first, outside-last order, and newly postmitotic neurons are specified to adopt the laminar positions characteristic of

sion in the LGE (Figure 2B).

telencephalon.

ent locations [74].

their birthdays [5;24;75].

**5.3. Neuronal specification**
