Abstract
Proper brain development requires precisely controlled phases of stem cell proliferation, lineage specification, differentiation, and migration. Lineage specification depends partly on concentration gradients of chemical cues called morphogens. However, the rostral brain (telencephalon) expands prominently during embryonic development, dynamically altering local morphogen concentrations, and telencephalic subregional properties develop with a time lag. Here, we investigated how progenitor specification occurs under these spatiotemporally changing conditions using a three-dimensional in vitro differentiation model. We verified the critical contributions of three signaling factors for the lineage specification of subregional tissues in the telencephalon, ventralizing sonic hedgehog (Shh) and dorsalizing bone morphogenetic proteins (BMPs) and WNT proteins (WNTs). We observed that a short-lasting signal is sufficient to induce subregional progenitors and that the timing of signal exposure for efficient induction is specific to each lineage. Furthermore, early and late progenitors possess different Shh signal response capacities. This study reveals a novel developmental mechanism for telencephalon patterning that relies on the interplay of dose- and time-dependent signaling, including a time lag for specification and a temporal shift in cellular Shh sensitivity. This delayed fate choice through two-phase specification allows tissues with marked size expansion, such as the telencephalon, to compensate for the changing dynamics of morphogen signals.
Highlights
The telencephalon is the most elaborate structure of the mammalian brain and is responsible for higher mental functions, such as memory, speech, value judgments, and sociality
Induction of four lineage fates was immunocytochemically distinguished in developing telencephalic organoids by the following marker expression patterns on day 10 in vitro: Pax6+/Foxg1+ for the dorsal telencephalon, Gsx2+/Foxg1+ for the dorsal half of the ventral telencephalon (LGE/caudal ganglionic eminence (CGE)), Nkx2-1+/Foxg1+ for the ventral-most telencephalon (MGE/preoptic area (POA)), and Lmx1a+/Foxg1− for the dorsal midline tissues (Supplementary Figures 1A– D,F,I)
According to the accepted patterning model based on positional information, the dose is a key determinant of morphogen response, such that tissues at short or long distances from a signal source are differentially induced or are both induced but by high and low doses of the signal, respectively (Wolpert, 1969; Campbell, 2003; Medina and Abellán, 2009)
Summary
The telencephalon is the most elaborate structure of the mammalian brain and is responsible for higher mental functions, such as memory, speech, value judgments, and sociality. These neural functions are achieved by complex neural networks composed of cells with distinct lineages and origins within the telencephalon. The cerebral cortex is composed of cells originating both internally and externally. The GE is further subdivided into three parts: the rostrally located lateral and medial ganglionic eminences (LGE and MGE) and the caudal ganglionic eminence (CGE)
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