14
telencephalic tissues using human PSCs will model not only human ventral fore-
brain development but also human disease pathology. Actually, transplantation stud-
ies using hPSC-derived cortical interneurons serve as a foundation for examining
cortical interneuron involvement in disease pathology (Maroof et al. 2013 ; Nicholas
et al. 2013 ). As a future aim, the induction of subtypes of human interneurons would
be useful for developing treatments for diseases resulting from interneuron
dysfunction.
1.4 Dorsalizing Telencephalic Tissues
1.4.1 Development of Dorsomedial Telencephalic Structure
In Vivo
In the more dorsomedial portion of the cerebral cortex, there are three distinct
regions: the choroid plexus, cortical hem, and medial pallium (Furuta et al. 1997 ;
Monuki et al. 2001 ; Arnold and Trojanowski 1996 ) (Fig. 1.6a). The most dorsome-
dial portion of dorsal telencephalon is the choroid plexus (Hébert et al. 2002 ). In
early development, choroid plexus is induced via BMP signals from the roof plate
(E9.0) (Hébert et al. 2002 ). Previous studies have showed that many BMP proteins
(such as BMP2, 4, 6, and 7) are expressed at the dorsal midline of telencephalon
with a signaling gradient and disrupting the BMP signaling led to a lack of choroid
plexus tissues, suggesting the necessity of BMP signaling in specifying dorsal tel-
encephalic cell fate (Cheng et al. 2006 ; Hébert et al. 2002 ) (Fig. 1.6a). In addition,
during the embryonic to adult phase, choroid plexus has essential developmental
and homeostatic roles regarding the generation of cerebrospinal fluid (CSF) and the
formation of the blood–CSF barrier (Lehtinen et al. 2013 ). The cortical hem is the
structure located next to choroid plexus, and it expresses several Wnt (Wnt 2b, 3a,
and 5a) and BMP (BMP 6 and 7) proteins that induce dorsomedial patterning of
dorsal telencephalon (Lee et al. 2000 ; Failli et al. 2002 ).
During development, it is the medial pallium that generates the hippocampus,
and it lies between the neocortex and the cortical hem (Arnold and Trojanowski
1996 ; Grove et al. 1998 ; Lee et al. 2000 ; Monuki et al. 2001 ; Tole et al. 1997 ; Zhao
et al. 1999 ) (Fig. 1.6a). The ability to form memories, during long-term tasks such
as learning and short-term tasks such as remembering a telephone number, relies on
the neuronal activity of the hippocampus (Geuze et al. 2005 ). During the embryonic
phase, Prox1+ hippocampal dentate granule (DG) neurons are first induced in the
dorsomedial edge of medial pallium (E12.5-), and they migrate along a curved tra-
jectory (E12.5–15.5). Then the cell fate of hippocampal CA neurons is determined
(CA3 (KA1+): E14.5- and CA1 (SCID+): E15.5-), resulting in the formation of a
typical hippocampal structure (Grove and Tole 1999 ) (Fig. 1.6a). Importantly, the
cortical hem is also known as the hippocampal organizer (Mangale et al. 2008 ).
When expression of Wnt 3a in the cortical hem was reduced using conditional
T. Kadoshima et al.