Each universe has a different pantheon of gods, who each represent and embody the fundamental aspects of reality. As they argue, the laws of physics and foundations upon which the perspectives and experiences of others are built change constantly in nigh imperceptible ways. However, as each universe's rules change differently, they drift apart, eventually becoming far enough apart for the differences to be discernible instantly by travelers.
Every setting in the Ascendant Multiverse has a different set of house rules. These house rules build on top of the foundation set by D&D 5e, but are optimized to evoke a unique feeling or theme of that setting:
Dungeons and Dystopia:
Primespace's ruleset is optimized to evoke a Scifi Dystopia feeling: with a Cyberpunk/Shadowrun theme at low levels, and a Science Fantasy theme at higher levels.
If you choose to start the Spelljammer campaign on Prima, the first arc of the campaign will be sparked by a corporate espionage mission.
Greyhawk:
Greyspace's ruleset is optimized to evoke a 1e/2e AD&D "dungeon-crawler" feeling.
If you choose to start the Spelljammer campaign on Oerth, the first arc of the campaign will center around a giant multi-level dungeon filled with traps, monsters, and riches.
Dragonlance:
Krynnspace's ruleset is optimized to evoke a D&D 3.5e/Pathfinder "high fantasy" feeling.
If you choose to start the Spelljammer campaign on Krynn, the first arc of the campaign will be a quest to defeat a great evil by rediscovering a lost secret of the gods.
Points of Light:
Pointspace's ruleset is optimized to evoke a D&D 4e feeling, with safe places being like "points of light strewn among the darkness."
If you choose to start the Spelljammer campaign on Nent, the first arc of the campaign will take the form of a metroidvania-esque mystery with exploration at the forefront. Backtracking with new information will almost certainly be required.
Forgotten Realms:
Realmspace's ruleset is optimized to follow how most people run D&D 5e: a narrative-heavy monster killing campaign. Maybe portions of OneD&D will be thrown in too.
If you choose to start the Spelljammer campaign on Toril, the first arc of the campaign will be a modified adaptation of an official WotC adventure module that goes off the rails when spelljamming is introduced.
Critical Role:
Rolespace's ruleset is optimized to evoke a feeling consistent with the Critical Role web series: a complex character-driven multilayered story.
If you choose to start the Spelljammer campaign on Exandria, the first arc of the campaign will be extremely personalized to your characters' backstories.
Eberron:
Shardspace's ruleset is optimized to evoke a steampunk/magipunk feeling, with heavy political and industrial themes.
If you choose to start the Spelljammer campaign on Eberron, the first arc of the campaign will be a longer and more dangerous journey than any other setting, further layered with politics and intrigue.
Voidspace:
In between crystal spheres, only the All Settings rules apply, though different regions of Voidspace may have strange quirks.
If you choose to start the Spelljammer campaign already on a spelljammer, the first arc of the campaign will be themed around cosmic horror.
Bear in mind as well that if you choose to create spelljamming characters to start with, intra-party balance may be an issue, as each setting has its own character creation rules. Later in the campaign, once a few of you have unique items and abilities acquired from various places, this should hopefully be less of an issue for replacement characters.
Also as a forewarning: at a certain point in the campaign, a cosmological-scale event will almost certainly occur, with the intention to bring Voidspace a lot closer to the new DnD 5e spelljammer lore. I won't spoil much, but I will say that after that point, a lot of the voidspace-centric restrictions on your characters will be lifted.